Substituted quinoxalines as positive allosteric modulators of mGluR4

ABSTRACT

The present invention relates to the use of novel quinoxaline derivatives of formula (I) 
                         
as positive allosteric modulators for modulating metabotropic glutamate receptor subtype 4 (mGluR4) and/or altering glutamate level or glutamatergic signalling.

TECHNICAL FIELD

The present invention relates to novel quinoxaline derivatives aspositive allosteric modulators for modulating metabotropic glutamatereceptor subtype 4 (mGluR4) and/or altering glutamate level orglutamatergic signalling.

PRIOR ART

Glutamate is the major amino-acid transmitter in the mammalian centralnervous system (CNS). Glutamate plays a major role in numerousphysiological functions, such as learning and memory but also sensoryperception, development of synaptic plasticity, motor control,respiration and regulation of cardiovascular function. Furthermore,glutamate is at the center of several different neurological andpsychiatric diseases, where there is an imbalance in glutamatergicneurotransmission.

Glutamate mediates synaptic neurotransmission through the activation ofionotropic glutamate receptor channels (iGluRs), namely the NMDA, AMPAand kainate receptors which are responsible for fast excitatorytransmission (Nakanishi et al., (1998) Brain Res. Rev., 26:230-235).

In addition, glutamate activates metabotropic glutamate receptors(mGluRs) which have a more modulatory role that contributes to thefine-tuning of synaptic efficacy. The mGluRs are G protein-coupledreceptors (GPCRs) with seven-transmembrane spanning domains and belongto GPCR family 3 along with the calcium-sensing, GABAb and pheromonereceptors. The mGluR family is composed of eight members. They areclassified into three groups (group I comprising mGluR1 and mGluR5;group II comprising mGluR2 and mGluR3; group III comprising mGluR4,mGluR6, mGluR7 and mGluR8) according to sequence homology,pharmacological profile and nature of intracellular signalling cascadesactivated (Schoepp et al., (1999) Neuropharmacology, 38: 1431-1476).

Glutamate activates the mGluRs through binding to the largeextracellular amino-terminal domain of the receptor, herein called theorthosteric binding site. This activation induces a conformationalchange of the receptor which results in the activation of the G-proteinand intracellular signalling pathways.

In the central nervous system, mGluR4 receptors are expressed mostintensely in the cerebellar cortex, basal ganglia, sensory relay nucleiof the thalamus and hippocampus (Bradley et al., (1999) Journal ofComparative Neurology, 407:33-46; Corti et al., (2002) Neuroscience, 110:403-420). The mGluR4 subtype is negatively coupled to adenylatecyclase via activation of the Gori/o protein, is expressed primarily onpresynaptic terminals, functioning as an autoreceptor or heteroceptorand activation of mGluR4 leads to decreases in transmitter release frompresynaptic terminals (Corti et al., (2002) Neuroscience, 1 10:403-420;Millan et al., (2002) Journal of Biological Chemistry, 277:47796-47803;Valenti et al., (2003) Journal of Neuroscience, 23:7218-7226).

Orthosteric agonists of mGluR4 are not selective and activate the otherGroup III mGluRs (Schoepp et al., (1999) Neuropharmacology, 38:1431-1476). The Group III orthosteric agonist L-AP4(L-2-amino-4-phosphonobutyrate) was able to reduce motor deficits inanimal models of Parkinson's disease (Valenti et al., (2003) J.Neurosci., 23:7218-7226) and decrease excitotoxicity (Bruno et al.,(2000) J. Neurosci., 20; 6413-6420) and these effects appear to bemediated through mGluR4 (Marino et al., (2005) Curr. Topics Med. Chem.,5:885-895). In addition to L-AP4, ACPT-1, another selective group IIImGluR agonist has been shown to cause a dose and structure-dependentdecrease in haloperidol-induced catalepsy and attenuatedhaloperidol-increased Proenkephalin mRNA expression in the striatum(Konieczny et al., (2007) Neuroscience, 145:61 1-620). Furthermore,Lopez et al. (2007, J. Neuroscience, 27:6701-671 1) have shown thatbilateral infusions of ACPT-I or L-AP4 into the globus pallidus fullyreversed the severe akinetic deficits produced by 6-hydroxydopaminelesions of nigrostriatal dopamine neurons in a reaction-time taskwithout affecting the performance of controls. In addition, the reversalof haloperidol-induced catalepsy by intrapallidal ACPT-1 was preventedby concomitant administration of a selective group III receptorantagonist (R5)-alpha-cyclopropyl-4-phosphonophenylglycine. The oppositeeffects produced by group III mGluR activation in the SNr stronglysuggest a role of mGluR4 rather than others mGluR receptor sub-types innormalizing basal ganglia activity (Lopez et al. 2007).

These results suggest that, among mGluR subtypes, mGluR4 is believed tobe the most interesting novel drug target for the treatment ofParkinson's disease (for a review see Conn et al., (2005) Nature ReviewNeuroscience, 6:787-798). Symptoms of Parkinson's disease appear to bedue to an imbalance in the direct and indirect output pathways of thebasal ganglia, and reduction of transmission at the inhibitory GABAergicstriato-pallidal synapse in the indirect pathway may result inalleviation of these symptoms (Marino et al., (2002) Amino Acids, 23:185-191). mGluR4 is more abundant in striato-pallidal synapses than instriato-nigral synapses, and its localization suggests function as apresynaptic heteroreceptor on GABAergic neurons (Bradley et al., (1999)Journal of Comparative Neurology, 407:33-46) suggesting that selectiveactivation or positive modulation of mGluR4 would decrease GABA releasein this synapse thereby decreasing output of the indirect pathway andreducing or eliminating the Parkinson's disease symptoms. Classicaltreatment of Parkinsonism typically involves the use of levodopacombined with carbidopa (SINEMET™) or benserazide (MADOPAR™). Dopamineagonists such as bromocriptine (PARLODEL™), lisuride and pergolide(CELANCE™) act directly on dopamine receptors and are also used for thetreatment of Parkinsonism. These molecules have the same side-effectprofile as levodopa.

The common end point of Parkinson's disease (PD) pathology is aprogressive degeneration of the dopaminergic neurons located in the parscompacta of the substantia nigra (SNpc) that project and releasedopamine into the striatum. PD symptoms usually appear when more than60% of SNpc neurons have already disappeared. This results in profoundmovements disturbances including rest tremor, rigidity and stiffness,gait and balance control dysfunctions and dementia that dramaticallydeteriorate patients and family quality of life.

Current treatments aim at substituting the missing dopamine or mimickingits effects by chronically providing patients with the dopamineprecursor L-DOPA, inhibitors of dopamine catabolic enzymes (MAOinhibitors) or direct dopamine receptors agonists. Although thesetreatments proved relatively efficient in controlling the main symptomsof PD, their chronic administration is associated with serious sideeffects. For example, the efficacy of L-DOPA following few years oftreatment invariably tends to diminish in intensity and stabilityleading to uneven on/off periods that require an increase in dosing. Inaddition, chronic administration of high doses of L-DOPA is associatedwith the occurrence of involuntary movements (dyskinesia) that areusually overcome by combining a reduction in the dose of L-DOPA withother dopaminergic agents. Yet, massive supply of dopamine in the brainhas also been associated with psychiatric disturbances includingdepression, psychotic symptoms, obsessive behaviours sleep disturbancesetc. Finally, none of the compounds of the current pharmacopeia for PDhave demonstrated neuroprotective activity that would delay diseaseprogression. Therefore, to address these important unmet medical needs,efforts are required to develop new treatments for PD that target theneurochemical systems downstream dopamine itself.

The control of movements by dopamine in healthy subjects follows acomplex pattern of neurochemical systems and brain structuresinteractions (Wichmann and Delong, 2003, Adv Neurol 91:9-18). The basalganglia that is composed mainly of the substantia nigra (SN), and thestriatal and thalamic complex constitutes the cornerstone of theseinteractions. The internal capsule of the globus pallidus (GPi) and SNpars reticulata (SNpr) fulfil the roles of relays between cortical areasthat directly control movements and the basal ganglia itself. GPi andSNpr receive both an inhibitory direct connection (direct pathway) andan excitatory indirect input (indirect pathway) from the basal ganglia.Both pathways are modulated by dopamine with opposite valence so thatthe direct pathway is stimulated while the indirect pathway is inhibitedby dopamine. Consequently in the diseased brain, the lack of dopamineleads to a dysregulation of the output activity of both the direct andindirect pathways. In particular, the indirect pathway getsoveractivated, which is reflected by increased GABA release into theglobus pallidus external segment (GPe). Consequently, glutamate releaseis increased in the SN pars compacta (SNpc), GPi and SNpr. Thesedistortions of the balance of neurotransmission in the direct andindirect pathways are believed to result in movement controlabnormalities and the precipitation of neurodegeneration of dopaminergicneurons. Fine analysis of these pathways provided insights on thepossibility to target neurochemical pathways downstream dopamine torestore its function in the PD brain without interfering directly withit. In particular, metabotropic glutamate receptors (mGluRs) have beenshown to modulate neurotransmitter release at the presynaptic level.Specifically, the subtype 4 of mGluR (mGluR4) predominantly expressed inthe brain in discrete areas was demonstrated to dampen glutamate andGABA neurotransmissions at the subthalamic nucleus (STN)—SNpc (Valenti Oet al., 2005, J Pharmacol Exp Ther 313:1296-1304) and striatum—GPe(Valenti Oet al., 2003, J Neurosci 23:7218-7226.) synapses,respectively. Evidence suggests that inhibition was achieved throughpresynaptic mechanisms providing a functional confirmation of theobserved presynaptic receptor localization (Corti et al., 2002,Neuroscience 110:403-420; Schoepp, 2001, J Pharmacol Exp Ther299:12-20).

Furthermore, behavioural analyses confirmed the beneficial effects ofstimulation of mGluR4 in both chronic and acute rat models of PD. Forexample, the cataleptic behaviour observed following haloperidoladministration and reserpine-induced immobility were both reversed bythe positive allosteric modulator (PAM) VU0155041 (Niswender et al.,2008, Mol Pharmacol 74:1345-1358). Both models mimic key features of thehuman disease that are rigidity and akinesia, respectively. Finally, theincreased release of glutamate is believed to participate, at least inpart, in the degeneration of the remaining dopaminergic neurons wherebyworsening the condition and reducing treatment efficacy. Hence, themGluR4 positive allosteric modulator (PAM) PHCCC, which reducesglutamate release, also protects neurons from further degenerating inrats treated with the neurotoxin 6-hydroxydopamine (6-OHDA) thatselectively destroys dopaminergic neurons (Vernon 2009, J Neurosci 29:12842-12844). Altogether these results suggest that stimulation ofmGluR4 has great potential to alleviate PD symptoms in patient andprovide neuroprotection to the remaining neurons.

A new avenue for developing selective compounds acting at mGluRs is toidentify molecules that act through allosteric mechanisms, modulatingthe receptor by binding to a site different from the highly conservedorthosteric binding site.

Positive allosteric modulators of mGluRs have emerged recently as novelpharmacological entities offering this attractive alternative. This typeof molecule has been discovered for mGluR1, mGluR2, mGluR4, mGluR5,mGluR7 and mGluR8 (Knoflach F. et al. (2001) Proc. Natl. Acad. Sci. USA,98: 13402-13407; Johnson M. P. et al., (2002) Neuropharmacology,43:799-808; O'Brien J. A. et al., (2003) Mol. Pharmacol., 64:731-740;Johnson M. P. et al, (2003) J. Med. Chem., 46:3189-3192; Marino M. J. etal., (2003) Proc. Natl. Acad. Sci. USA, 100: 13668-13673; Mitsukawa etal., (2005) Proc. Natl. Acad. Sci. USA, 102(51): 18712-18717; Wilson J.et al., (2005) Neuropharmacology, 49:278; for a review see Mutel V.,(2002) Expert Opin. Ther. Patents, 12: 1-8; Kew J. N., (2004) Pharmacol.Ther., 104(3):233-244; Johnson M. P. et al., (2004) Biochem. Soc.Trans., 32:881-887; recently Ritzen A., Mathiesen, J. M. and Thomsen C,(2005) Basic Clin. Pharmacol. Toxicol., 97:202-213).

In particular molecules have been described as mGluR4 positiveallosteric modulators (Maj et al., (2003) Neuropharmacology, 45:895-906;Mathiesen et al., (2003) British Journal of Pharmacology, 138:1026-1030). It has been demonstrated that such molecules have beencharacterized in in vitro systems as well as in rat brain slices wherethey potentiated the effect of L-AP4 in inhibiting transmission at thestriatopallidal synapse. These compounds do not activate the receptor bythemselves (Marino et al., (2003) Proc. Nat. Acad. Sci. USA, 100:13668-13673). Rather, they enable the receptor to produce a maximalresponse to a concentration of glutamate or the Group III orthostericagonist L-AP4 which by itself induces a minimal response.

PHCCC (N-phenyl-7-(hydroxyimino)cyclopropa[6]chromen-la-carboxamide), apositive allosteric modulator of mGluR4 not active on other mGluRs (Majet al., (2003) Neuropharmacology, 45:895-906), has been shown to beefficacious in animal models of Parkinson's disease thus representing apotential novel therapeutic approach for Parkinson's disease as well asfor other motor disorders and disturbances (Marino et al., (2003) Proc.Nat. Acad. Sci. USA, 100: 13668-13673), neurodegeneration in Parkinson'sdisease (Marino et al., (2005) Curr. Topics Med. Chem., 5:885-895;Valenti et al., (2005) J. Pharmacol. Exp. Ther., 313: 1296-1304; Vernonet al., (2005) Eur. J. Neurosci., 22: 1799-1806, Battaglia et al.,(2006) J. Neurosci., 26:7222-7229), and neurodegeneration in Alzheimer'sdisease or due to ischemic or traumatic insult (Maj et al., (2003)Neuropharmacology, 45:895-906).

PHCCC also has been shown to be active in an animal model of anxiety(Stachowicz et al., (2004) Eur. J. Pharmacol., 498: 153-156).Previously, ACPT-1 has been shown to produce a dose-dependentanti-conflict effect after intrahippocampal administration andanti-depressant-like effects in rats after intracerebroventricularadministration (Tatarczynska et al., (2002) Pol. J. Pharmacol.,54(6):707-710). More recently, ACPT-1 has also been shown to haveanxiolytic-like effects in the stress-induced hyperthermia, in theelevated-plus maze in mice and in the Vogel conflict test in rats wheninjected intraperitoneally (Stachowicz et al., (2009) Neuropharmacology,57(3): 227-234).

Activation of mGluR4 receptors which are expressed in a- and F-cells inthe islets of Langerhans inhibits glucagon secretion. Molecules whichactivate or potentiate the agonist activity of these receptors may be aneffective treatment for hyperglycemia, one of the symptoms of type 2diabetes (Uehara et al., (2004) Diabetes, 53:998-1006).

The [beta]-chemokine RANTES is importantly involved in neuronalinflammation and has been implicated in the pathophysiology of multiplesclerosis. Activation of Group III mGluRs with L-AP4 reduced thesynthesis and release of RANTES in wild-type cultured astrocytes,whereas the ability of L-AP4 to inhibit RANTES was greatly decreased inastrocyte cultures from mGluR4 knockout mice (Besong et al., (2002)Journal of Neuroscience, 22:5403-541 1). These data suggest thatpositive allosteric modulators of mGluR4 may be an effective treatmentfor neuroinflammatory disorders of the central nervous system, includingmultiple sclerosis and related disorders.

Two different variants of the mGluR4 receptor are expressed in tastetissues and may function as receptors for the umami taste sensation(Monastyrskaia et al., (1999) Br. J Pharmacol., 128: 1027-1034; Toyonoet al., (2002) Arch. Histol. Cytol., 65:91-96). Thus positive allostericmodulators of mGluR4 may be useful as taste agents, flavour agents,flavour enhancing agents or food additives.

There is anatomical evidence that the majority of vagal afferentsinnervating gastric muscle express group Ill mGluRs (mGluR4, mGluR6,mGluR7 and mGluR8) and actively transport receptors to their peripheralendings (Page et al., (2005) Gastroenterology, 128:402-10). Recently, itwas shown that the activation of peripheral group III mGluRs inhibitedvagal afferents mechanosensitivity in vitro which translates intoreduced triggering of transient lower esophageal sphincter relaxationsand gastroesophageal reflux in vivo (Young et al., (2008)Neuropharmacol, 54:965-975). Labelling for mGluR4 and mGluR8 wasabundant in gastric vagal afferents in the nodose ganglion, at theirtermination sites in the nucleus tractus solitarius and in gastric vagalmotoneurons. These data suggest that positive allosteric modulators ofmGluR4 may be an effective treatment for gastroesophageal reflux disease(GERD) and lower esophageal disorders and gastro-intestinal disorders.

For groups III mGluRs, examples of allosteric modulators were so fardescribed for the mGluR subtype 4 (mGluR4). PHCCC, MPEP and S1B1893 (MajM et al., Neuropharmacology, 45(7), 895-903, 2003; Mathiesen J M et al.,Br. J, Pharmacol. 138(6), 1026-30, 2003) were the first ones describedin 2003. More recently, more potent positive allosteric modulators werereported in the literature (Niswender C M et al., Mol. Pharmacol. 74(5),1345-58, 2008; Niswender C M et al., Bioorg. Med. Chem. Lett 18(20),5626-30, 2008; Williams R et al., Bioorg. Med. Chem. Lett. 19(3), 962-6,2009; Engers D W et al., J. Med. Chem. May 27, 2009) and in two patentpublications describing families of amido and heteroaromatic compounds(WO 2009/010454 and WO 2009/010455).

Numerous studies have already described the potential applications ofmGluR modulators in neuroprotection (see Bruno V et al., J. Cereb. BloodFlow Metab., 21 (9), 1013-33, 2001 for review). For instance, antagonistcompounds of group I mGluRs showed interesting results in animal modelsfor anxiety and postischemic neuronal injury (Pile A et al.,Neuropharmacology, 43(2), 181-7, 2002; Meli E et al., Pharmacol.Biochem. Behav., 73(2), 439-46, 2002), agonists of group II mGluRsshowed good results in animal models for Parkinson and anxiety(Konieczny J et al., Naunyn-Schmlederbergs Arch. Pharmacol., 358(4),500-2, 1998).

Group III mGluR modulators showed positive results in several animalmodels of schizophrenia (Paiucha-Poniewiera A et al., Neuropharmacology,55(4), 517-24, 2008) and chronic pain (Goudet C et al., Pain, 137(1), 112-24, 2008; Zhang H M et al., Neuroscience, 158(2), 875-84, 2009).

Group III mGluR were also shown to exert the excitotoxic actions ofhomocysteine and homocysteic acid contributing to the neuronal pathologyand immunosenescence that occur in Alzheimer Disease (Boldyrev A andJohnson P, J. Alzheimers Dis. 1 (2), 219-28, 2007).

Moreover, group III mGluR modulators showed promising results in animalmodels of Parkinson and neurodegeneration (Conn J et al., Nat Rev.Neuroscience, 6(10), 787-98, 2005 for review; Vernon A C et al., J.Pharmacol. Exp. Then, 320(1), 397-409, 2007; Lopez S et al.,Neuropharmacology, 55(4), 483-90, 2008; Vernon A C et al., Neuroreport,19(4), 475-8, 2008). It was further demonstrated with selective ligandsthat the mGluR subtype implicated in these antiparkinsonian andneuroprotective effects was mGluR4 (Marino M J et al., Proc. Natl. Acad.Sci. USA 100(23), 13668-73, 2003; Battaglia G et al., J. Neurosci.26(27), 7222-9, 2006; Niswender C M et al., Mol. Pharmacol. 74(5),1345-58, 2008).

mGluR4 modulators were also shown to exert anxiolytic activity(Stachowicz K et al., Eur. J. Pharmacol., 498(1-3), 153-6, 2004) andanti-depressive actions (Palucha A et al., Neuropharmacology 46(2),151-9, 2004; Klak K et al., Amino Acids 32(2), 169-72, 2006).

In addition, mGluR4 were also shown to be involved in glucagon secretioninhibition (Uehara S., Diabetes 53(4), 998-1006, 2004). Therefore,orthosteric or positive allosteric modulators of mGluR4 have potentialfor the treatment of type 2 diabetes through its hypoglycemic effect.

Moreover, mGluR4 was shown to be expressed in prostate cancer cell-line(Pessimissis N et al., Anticancer Res. 29(1), 371-7, 2009) or colorectalcarcinoma (Chang H J et al., CIL Cancer Res. 1 1 (9), 3288-95, 2005) andits activation with PHCCC was shown to inhibit growth ofmedulloblastomas (Iacoveili L et al., J. Neurosci. 26(32) 8388-97,2006), mGluR4 modulators may therefore have also potential role for thetreatment of cancers.

Finally, receptors of the umami taste expressed in taste tissues wereshown to be variants of the rnGluR4 receptor (Eschle B K., Neuroscience,155(2), 522-9, 2008). As a consequence, mGluR4 modulators may also beuseful as taste agents, flavour agents, flavour enhancing agents or foodadditives.

Further prior art documents are as follows:

WO 99/42461 and WO 99/42463 describe substituted quinoxaline derivativesas IL-8 receptor antagonists.

WO 2000/042026 describes quinoxalines as non-peptide GLP-1 agonists.

WO 2002/083138 is directed among others inhibitors of Akt activity.

WO 2003/086394 deals with among others quinoxalines as inhibitors of Aktactivity.

WO 2005/007099 relates to PKB inhibitors as anti-tumor agents.

US 2005/0026923 discloses quinoxalinecarboxamides as antivirals.

WO 2006/040568 is directed to quioxalines as B-Raf inhibitors.

WO 2006/091395 describes among others quinoxalines as inhibitors of Aktactivity.

WO 2009/021083 deals with quinoxaline derivatives as PI3 kinaseinhibitors.

WO 2010/093808 relates to quioxaline compounds as selective kinaseinhibitors.

WO 2011/028947 is directed to heterocyclic compounds for the inhibitionof PAS kinase.

WO 2011/094708 deals with small molecules for the modulation of MCL-1.

WO 2011/127333 relates to compound targeting CXCR4 and a G protein fortreating diseases.

WO 2012/065139 discloses ENTPD5 inhibitors.

WO 2012/071414 describes quinoxaline compounds and their use.

WO 2012/087861 is directed to quinoxaline and azaquinoxaline derivativesfor use as CRTH2 receptor modulators.

US 2012/0225863 deals with heterocyclic compounds for the inhibition ofPAS kinase.

WO 2012/094462 relates to heterocyclic compounds for the inhibition ofPAS kinase.

The citation of any reference in this application is not an admissionthat the reference is relevant prior art to this application.

DESCRIPTION OF THE INVENTION

The present invention has the object to provide novel quinoxalinederivatives.

The object of the present invention has surprisingly been solved in oneaspect by providing compounds of formula (I)

wherein:

-   -   X independently from each other denotes N or C, with the proviso        that only one X is N or no X is N;    -   R₁, R₂ independently from each other denote aryl, heteroaryl or        heterocyclyl, which can optionally be substituted by one or more        identical or different substituents T;    -   R_(3a), R_(3b), R_(4a), independently from each other denotes        substituent T,    -   R_(4b), R_(5b), R_(5b), if the individual X is C; if the        individual X is N, then one    -   R_(6a), R_(6b) of the R_(3/4/5/6a/b) substituents is absent and        the other one of the R_(3/4/5/6a/b) substituents denotes        substituent T or forms a double bond with one of the        R_(3/4/5/6a/b) substituents of an adjacent X;    -   T denotes independently from each other H, alkyl, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl, heterocyclylalkyl, halogen, F, Cl, Br, I, OH, CN,        NO₂, NYY, CF₃, OCF₃, alkyl-OH, alkyl-NYY, alkyl-CN, O-alkyl,        O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl,        O-heteroaryl, O-alkyl-heteroaryl, O-heterocyclyl,        O-alkyl-heterocyclyl, C(O)-alkyl, C(O)-cycloalkyl,        C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl,        C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl,        C(O)-alkyl-heterocyclyl, C(O)O-alkyl, C(O)O-cycloalkyl,        C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl,        C(O)O-heteroaryl, C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl,        C(O)O-alkyl-heterocyclyl, C(O)NH-alkyl, C(O)NH-cycloalkyl,        C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl, C(O)NH-alkyl-aryl,        C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl, C(O)NH-heterocyclyl,        C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl, NHC(O)-cycloalkyl,        NHC(O)-alkyl-cycloalkyl, NHC(O)-aryl, NHC(O)-alkyl-aryl,        NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl, NHC(O)-heterocyclyl,        NHC(O)-alkyl-heterocyclyl, O-alkyl-NYY, C(O)H, C(O)OY,        C(O)NY-alkyl-NYY, C(O)NYY, wherein alkyl, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl and heterocyclylalkyl moieties can optionally be        substituted by one or more identical or different substituents        Z;    -   Y denotes independently from each other H, alkyl, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl, heterocyclylalkyl, wherein alkyl, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl and heterocyclylalkyl can optionally be substituted        by one or more identical or different substituents Z;    -   Z denotes independently from each other alkyl, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,        heterocyclyl, heterocyclylalkyl, halogen, F, Cl, Br, I, OH, CN,        NO₂, NH₂, NH-alkyl, N(alkyl)₂, NH-alkyl-OH, NH-alkyl-O-alkyl,        NH-alkyl-aryl, CF₃, OCF₃, alkyl-OH, alkyl-NH₂, alkyl-NH-alkyl,        alkyl-N(alkyl)₂, alkyl-CN, alkyl-C(O)—heterocyclyl, O-alkyl,        O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl,        O-heteroaryl, O-alkyl-heteroaryl, O-heterocyclyl,        O-alkyl-heterocyclyl, O-alkyl-NH₂, C(O)H, C(O)OH,        C(O)NH-alkyl-NH₂, C(O)NH₂, C(O)—C(O)—NH₂, C(O)-alkyl-NH-alkyl,        C(O)-alkyl-NH-alkyl-O-alkyl, C(O)-alkyl, C(O)-cycloalkyl,        C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl,        C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl,        C(O)-alkyl-heterocyclyl, C(O)-heterocyclyl-alkyl, C(O)O-alkyl,        C(O)O-cycloalkyl, C(O)O-alkyl-cycloalkyl, C(O)O-aryl,        C(O)O-alkyl-aryl, C(O)O-heteroaryl, C(O)O-alkyl-heteroaryl,        C(O)O-heterocyclyl, C(O)O-alkyl-heterocyclyl, C(O)NH-alkyl,        C(O)NH-cycloalkyl, C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl,        C(O)NH-alkyl-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl,        C(O)NH-heterocyclyl, C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl,        NHC(O)-cycloalkyl, NHC(O)-alkyl-cycloalkyl, NHC(O)-aryl,        NHC(O)-alkyl-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl,        NHC(O)-heterocyclyl, NHC(O)-alkyl-heterocyclyl,        C(O)NH-aryl-halogen, C(O)NH-aryl-O-alkyl, C(O)N(alkyl)-aryl,        C(O)N(aryl)₂, S-alkyl, S-cycloalkyl, S-alkyl-cycloalkyl, S-aryl,        S-alkyl-aryl, S-heteroaryl, S-alkyl-heteroaryl, S-heterocyclyl,        S-alkyl-heterocyclyl;    -   and the physiologically acceptable salts, solvates, tautomers        and stereoisomers thereof, including mixtures thereof in all        ratios.

In a preferred embodiment, a compound according to formula (I) isprovided, wherein:

-   -   denotes

-   -   and the physiologically acceptable salts, solvates, tautomers        and stereoisomers thereof, including mixtures thereof in all        ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein:

-   -   R₁, R₂ independently from each other denote phenyl, furanyl,        pyridinyl, thiophenyl, pyrrolidinyl, naphthalenyl, morpholinyl,        piperazinyl, azetidinyl, piperidinyl, quinolinyl, indolyl,        indazolyl or benzooxazolonyl, which can optionally be        substituted by one or more identical or different substituents        T;    -   and the physiologically acceptable salts, solvates, tautomers        and stereoisomers thereof, including mixtures thereof in all        ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein:

-   -   R₁, R₂ independently from each other are selected from the group        consisting of: phenyl, furan-2-yl, furan-3-yl,        4-dimethylamino-phenyl, 2-fluorophenyl, 4-fluorophenyl,        pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4-hydroxy-phenyl,        thiophen-2-yl, thiophen-3-yl, 4-methoxy-phenyl, 4-ethoxy-phenyl,        4-ethyl-phenyl, 4-fluoro-3-methyl-phenyl,        4-methylsulfanyl-phenyl, 4-trifluoromethoxy-phenyl,        3,4-difluorophenyl, 4-benzaldehyde, 4-tert-butyl-phenyl,        4-isopropyl-phenyl, pyrrolidin-1-yl, 3-chloro-4-methoxy-phenyl,        3-chloro-4-methyl-phenyl, 4-cyanomethyl-phenyl,        2-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl,        6-methoxy-naphthalen-1-yl, 3,4-dichlorophenyl, morpholin-4-yl,        4-dimethylamino-phenyl, 4-methyl-piperazin-1-yl, azetidin-1-yl,        piperidin-1-yl, quinolin-4-yl, quinolin-8-yl,        4-hydroxymethyl-piperidin-1-yl, 4-hydroxy-piperidin-1-yl,        indol-4-yl, 4-acetamide, 4-(2,2,2-trifluoro)-acetamide,        4-amino-phenyl, indazol-5-yl, 4-hydroxymethyl-phenyl,        benzooxazol-2-one-6-yl;    -   and the physiologically acceptable salts, solvates, tautomers        and stereoisomers thereof, including mixtures thereof in all        ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein:

-   -   T denotes independently from each other H, fluoro, chloro,        methyl, methoxy, hydroxy, ethoxy, isopropoxy, hydroxyl-methyl,        methyl-carbonyl, 4-methyl-piperidin-1-yl-carbonyl,        morpholin-4-yl-carbonyl, 4-methyl-piperazin-1-yl-carbonyl,        (2-hydroxy-1,1-dimethyl-ethyl)-carboxylic acid amide,        pyrrolidin-1-yl-carbonyl, carboxylic acid cyclopentylamide,        piperidin-1-yl-carbonyl, carboxylic acid cyclohexylamide,        azetidin-1-yl-carbonyl, carboxylic acid cyclohexylmethylamide,        carboxylic acid (3-methyl-butyl)-amide, carboxylic acid        (5-methyl-isoxazol-3-yl)-amide, carboxylic acid        pyridin-2-ylamide, carboxylic acid pyridin-3-ylamide, carboxylic        acid pyridin-4-ylamide, carboxylic acid        (4-hydroxy-cyclohexyl)-amide, carboxylic acid        (2-cyano-ethyl)-amide, carboxylic acid (2-hydroxy-propyl)-amide,        carboxylic acid cyclopropylmethyl-amide, carboxylic acid        methylamide, carboxylic acid dimethylamide, carboxylic acid        (2-hydroxy-ethyl)-amide, carboxylic acid        (2-hydroxy-1-methyl-ethyl)-amide, carboxylic acid        thiazol-2-ylamide, carboxylic acid ethyl ester, carboxylic acid        isopropyl ester, carboxylic acid        [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide, carboxylic acid        (2-dimethylamino-ethyl)-amide, carboxylic acid        (6-chloro-benzothiazol-2-yl)-amide, methoxymethyl,        4-methyl-piperazin-1-yl-methyl, morpholin-4-ylmethyl,        pyrrolidin-1-yl-methyl, 4-hydroxy-piperdin-1-yl,        [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-aminomethyl,        methylaminomethyl, 2-pyrrolidin-1-yl-ethoxy,        1-methyl-pyrrolidin-3-yloxy, 4-methyl-piperazin-1-yl)-propoxy,        2-dimethylamino-ethyloxy, 3-dimethylamino-propyloxy,        4-methyl-piperazin-1-yl)-ethoxy, 2-morpholin-4-yl-ethoxy,        3-morpholin-4-yl-propoxy, 1-methyl-tetrazol-5-yl,        2-methyl-tetrazol-5-yl;    -   and the physiologically acceptable salts, solvates, tautomers        and stereoisomers thereof, including mixtures thereof in all        ratios.

In a preferred embodiment, a compound according to formula (I) and aboveembodiments is provided, wherein:

-   -   denotes

-   -   R₁, R₂ independently from each other are selected from the group        consisting of: phenyl, furan-2-yl, furan-3-yl,        4-dimethylamino-phenyl, 2-fluorophenyl, 4-fluorophenyl,        pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 4-hydroxy-phenyl,        thiophen-2-yl, thiophen-3-yl, 4-methoxy-phenyl, 4-ethoxy-phenyl,        4-ethyl-phenyl, 4-fluoro-3-methyl-phenyl,        4-methylsulfanyl-phenyl, 4-trifluoromethoxy-phenyl,        3,4-difluorophenyl, 4-benzaldehyde, 4-tert-butyl-phenyl,        4-isopropyl-phenyl, pyrrolidin-1-yl, 3-chloro-4-methoxy-phenyl,        3-chloro-4-methyl-phenyl, 4-cyanomethyl-phenyl,        2-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl,        6-methoxy-naphthalen-1-yl, 3,4-dichlorophenyl, morpholin-4-yl,        4-dimethylamino-phenyl, 4-methyl-piperazin-1-yl, azetidin-1-yl,        piperidin-1-yl, quinolin-4-yl, quinolin-8-yl,        4-hydroxymethyl-piperidin-1-yl, 4-hydroxy-piperidin-1-yl,        indol-4-yl, 4-acetamide, 4-(2,2,2-trifluoro)-acetamide,        4-amino-phenyl, indazol-5-yl, 4-hydroxymethyl-phenyl,        benzooxazol-2-one-6-yl;    -   T denotes independently from each other H, fluoro, chloro,        methyl, methoxy, hydroxy, ethoxy, isopropoxy, hydroxyl-methyl,        methyl-carbonyl, 4-methyl-piperidin-1-yl-carbonyl,        morpholin-4-yl-carbonyl, 4-methyl-piperazin-1-yl-carbonyl,        (2-hydroxy-1,1-dimethyl-ethyl)-carboxylic acid amide,        pyrrolidin-1-yl-carbonyl, carboxylic acid cyclopentylamide,        piperidin-1-yl-carbonyl, carboxylic acid cyclohexylamide,        azetidin-1-yl-carbonyl, carboxylic acid cyclohexylmethylamide,        carboxylic acid (3-methyl-butyl)-amide, carboxylic acid        (5-methyl-isoxazol-3-yl)-amide, carboxylic acid        pyridin-2-ylamide, carboxylic acid pyridin-3-ylamide, carboxylic        acid pyridin-4-ylamide, carboxylic acid        (4-hydroxy-cyclohexyl)-amide, carboxylic acid        (2-cyano-ethyl)-amide, carboxylic acid (2-hydroxy-propyl)-amide,        carboxylic acid cyclopropylmethyl-amide, carboxylic acid        methylamide, carboxylic acid dimethylamide, carboxylic acid        (2-hydroxy-ethyl)-amide, carboxylic acid        (2-hydroxy-1-methyl-ethyl)-amide, carboxylic acid        thiazol-2-ylamide, carboxylic acid ethyl ester, carboxylic acid        isopropyl ester, carboxylic acid        [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide, carboxylic acid        (2-dimethylamino-ethyl)-amide, carboxylic acid        (6-chloro-benzothiazol -2-yl)-amide, methoxymethyl,        4-methyl-piperazin-1-yl-methyl, morpholin-4-ylmethyl,        pyrrolidin-1-yl-methyl, 4-hydroxy-piperdin-1-yl,        [2-(1-methyl-pyrrolidin-2-yl)-ethyl]-aminomethyl,        methylaminomethyl, 2-pyrrolidin-1-yl-ethoxy,        1-methyl-pyrrolidin-3-yloxy, 4-methyl-piperazin-1-yl)-propoxy,        2-dimethylamino-ethyloxy, 3-dimethylamino-propyloxy,        4-methyl-piperazin-1-yl)-ethoxy, 2-morpholin-4-yl-ethoxy,        3-morpholin-4-yl-propoxy, 1-methyl-tetrazol-5-yl,        2-methyl-tetrazol-5-yl;    -   and the physiologically acceptable salts, solvates, tautomers        and stereoisomers thereof, including mixtures thereof in all        ratios.

In another aspect, the object of the present invention has surprisinglybeen solved by providing compounds selected from the group consistingof:

Com- pound No. Chemical Structure Chemical Name 1

2-Phenyl-3-quinolin- 4-yl-quinoxaline 2

4-(3-Phenyl-quinoxalin- 2-yl)-phenol 3

1-(3-Phenyl-quinoxalin- 2-yl)-piperidin-4-ol 4

2-(3,4-Difluoro-phenyl)- 3-(1H-indol-4-yl)- quinoxaline 5

5-Methyl-2,3-diphenyl- quinoxaline 6

2-Phenyl-3-quinolin- 8-yl-quinoxaline 7

1-(2,3-Diphenyl- quinoxalin-5-yl)- ethanone 8

2,3-Diphenyl-5,6,7,8- tetrahydro-quinoxaline 9

2,3-Bis-(2-fluoro- phenyl)-quinoxaline 10 

2-(3,4-Difluoro- phenyl)-3- phenyl-quinoxaline

-   -   and the physiologically acceptable salts, solvates, tautomers        and stereoisomers thereof, including mixtures thereof in all        ratios.

For the avoidance of doubt, if chemical name and chemical structure ofthe above illustrated compounds do not correspond by mistake, thechemical structure is regarded to unambiguously define the compound.

All the above generically or explicitly disclosed compounds, includingpreferred subsets/embodiments of the herein disclosed formula (I) andCompounds 1 to 10, are hereinafter referred to as compounds of the(present) invention.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC organisation for chemical compounds and especially organiccompounds.

The terms indicated for explanation of the above compounds of theinvention always, unless indicated otherwise in the description or inthe claims, have the following meanings:

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents.

The term “substituted” means that the corresponding radical, group ormoiety has one or more substituents. Where a radical has a plurality ofsubstituents, and a selection of various substituents is specified, thesubstituents are selected independently of one another and do not needto be identical.

The terms “alkyl” or “A” as well as other groups having the prefix “alk”for the purposes of this invention refer to acyclic saturated orunsaturated hydrocarbon radicals which may be branched or straight-chainand preferably have 1 to 10 carbon atoms, i.e. C₁-C₁₀-alkanyls,C₂-C₁₀-alkenyls and C₂-C₁₀-alkynyls. Alkenyls have at least one C—Cdouble bond and alkynyls at least one C—C triple bond. Alkynyls mayadditionally also have at least one C—C double bond. Examples ofsuitable alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl,tert-pentyl, 2- or 3-methyl-pentyl, n-hexyl, 2-hexyl, isohexyl,n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl,n-hexadecyl, n-octadecyl, n-icosanyl, n-docosanyl, ethylenyl (vinyl),propenyl (—CH₂CH═CH₂; —CH═CH—CH₃, —C(═CH₂)—CH₃), butenyl, pentenyl,hexenyl, heptenyl, octenyl, octadienyl, octadecenyl, octadec-9-enyl,icosenyl, icos-11-enyl, (Z)-icos-11-enyl, docosnyl, docos-13-enyl,(Z)-docos-13-enyl, ethynyl, propynyl (—CH₂—C≡CH, —C≡C—CH₃), butynyl,pentynyl, hexynyl, heptynyl, octynyl. Especially preferred isC₁₋₄-alkyl. A C₁₋₄-alkyl radical is for example a methyl, ethyl, propyl,isopropyl, butyl, isobutyl, tert-butyl.

The term “cycloalkyl” for the purposes of this invention refers tosaturated and partially unsaturated non-aromatic cyclic hydrocarbongroups/radicals, having 1 to 3 rings, that contain 3 to 20, preferably 3to 12, most preferably 3 to 8 carbon atoms. The cycloalkyl radical mayalso be part of a bi- or polycyclic system, where, for example, thecycloalkyl radical is fused to an aryl, heteroaryl or heterocyclylradical as defined herein by any possible and desired ring member(s).The bonding to the compounds of the general formula can be effected viaany possible ring member of the cycloalkyl radical. Examples of suitablecycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl,cyclopentenyl and cyclooctadienyl. Especially preferred areC₃-C₉-cycloalkyl and C₄-C₈-cycloalkyl. A C₄-C₈-cycloalkyl radical is forexample a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

The term “heterocyclyl” or “heterocycle” for the purposes of thisinvention refers to a mono- or polycyclic system of 3 to 20, preferably5 or 6 to 14 ring atoms comprising carbon atoms and 1, 2, 3, 4, or 5heteroatoms, in particular nitrogen, oxygen and/or sulfur which areidentical or different. The cyclic system may be saturated, mono- orpolyunsaturated but may not be aromatic. In the case of a cyclic systemconsisting of at least two rings the rings may be fused or spiro- orotherwise connected. Such “heterocyclyl” radicals can be linked via anyring member. The term “heterocyclyl” also includes systems in which theheterocycle is part of a bi- or polycyclic saturated, partiallyunsaturated and/or aromatic system, such as where the heterocycle isfused to an “aryl”, “cycloalkyl”, “heteroaryl” or “heterocyclyl” groupas defined herein via any desired and possible ring member of theheterocycyl radical. The bonding to the compounds of the general formulacan be effected via any possible ring member of the heterocycyl radical.Examples of suitable “heterocyclyl” radicals are pyrrolidinyl,thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl,oxapiperidinyl, oxadiazolyl, tetrahydrofuryl, imidazolidinyl,thiazolidinyl, tetrahydropyranyl, morpholinyl, tetrahydrothiophenyl,dihydropyranyl, indolinyl, indolinylmethyl, imidazolidinyl,2-aza-bicyclo[2.2.2]octanyl.

The term “aryl” for the purposes of this invention refers to a mono- orpolycyclic aromatic hydrocarbon systems having 3 to 14, preferably 5 to14, more preferably 5 to 10 carbon atoms. The term “aryl” also includessystems in which the aromatic cycle is part of a bi- or polycyclicsaturated, partially unsaturated and/or aromatic system, such as wherethe aromatic cycle is fused to an “aryl”, “cycloalkyl”, “heteroaryl” or“heterocyclyl” group as defined herein via any desired and possible ringmember of the aryl radical. The bonding to the compounds of the generalformula can be effected via any possible ring member of the arylradical. Examples of suitable “aryl” radicals are phenyl, biphenyl,naphthyl, 1-naphthyl, 2-naphthyl and anthracenyl, but likewise indanyl,indenyl, or 1,2,3,4-tetrahydronaphthyl. The most preferred aryl isphenyl.

The term “heteroaryl” for the purposes of this invention refers to a 3to 15, preferably 5 to 14, more preferably 5-, 6- or 7-membered mono- orpolycyclic aromatic hydrocarbon radical which comprises at least 1,where appropriate also 2, 3, 4 or 5 heteroatoms, preferably nitrogen,oxygen and/or sulfur, where the heteroatoms are identical or different.The number of nitrogen atoms is preferably 0, 1, 2, or 3, and that ofthe oxygen and sulfur atoms is independently 0 or 1. The term“heteroaryl” also includes systems in which the aromatic cycle is partof a bi- or polycyclic saturated, partially unsaturated and/or aromaticsystem, such as where the aromatic cycle is fused to an “aryl”,“cycloalkyl”, “heteroaryl” or “heterocyclyl” group as defined herein viaany desired and possible ring member of the heteroaryl radical. Thebonding to the compounds of the general formula can be effected via anypossible ring member of the heteroaryl radical. Examples of suitable“heteroaryl” are acridinyl, benzdioxinyl, benzimidazolyl,benzisoxazolyl, benzodioxolyl, benzofuranyl, benzothiadiazolyl,benzothiazolyl, benzothienyl, benzoxazolyl, carbazolyl, cinnolinyl,dibenzofuranyl, dihydrobenzothienyl, furanyl, furazanyl, furyl,imidazolyl, indazolyl, indolinyl, indolizinyl, indolyl,isobenzylfuranyl, isoindolyl, isoquinolinyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, phenazinyl,phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridyl, pyrimidinyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl, quinolyl, quinoxalinyl,tetrazolyl, thiadiazolyl, thiazolyl, thienyl, thiophenyl, triazinyl,triazolyl.

For the purposes of the present invention, the terms “alkyl-cycloalkyl”,“cycloalkylalkyl”, “alkyl-heterocyclyl”, “heterocyclylalkyl”,“alkyl-aryl”, “arylalkyl”, “alkyl-heteroaryl” and “heteroarylalkyl” meanthat alkyl, cycloalkyl, heterocycl, aryl and heteroaryl are each asdefined above, and the cycloalkyl, heterocyclyl, aryl and heteroarylradical is bonded to the compounds of the general formula via an alkylradical, preferably C₁-C₈-alkyl radical, more preferably C₁-C₄-alkylradical.

The term “alkyloxy” or “alkoxy” for the purposes of this inventionrefers to an alkyl radical according to above definition that isattached to an oxygen atom. The attachment to the compounds of thegeneral formula is via the oxygen atom. Examples are methoxy, ethoxy andn-propyloxy, propoxy, isopropoxy. Preferred is “C₁-C₄-alkyloxy” havingthe indicated number of carbon atoms.

The term “cycloalkyloxy” or “cycloalkoxy” for the purposes of thisinvention refers to a cycloalkyl radical according to above definitionthat is attached to an oxygen atom. The attachment to the compounds ofthe general formula is via the oxygen atom. Examples are cyclopropyloxy,cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy,cyclooctyloxy. Preferred is “C₃-C₉cycloalkyloxy” having the indicatednumber of carbon atoms.

The term “heterocyclyloxy” for the purposes of this invention refers toa heterocyclyl radical according to above definition that is attached toan oxygen atom. The attachment to the compounds of the general formulaeis via the oxygen atom. Examples are pyrrolidinyloxy,thiapyrrolidinyloxy, piperidinyloxy, piperazinyloxy.

The term “aryloxy” for the purposes of this invention refers to an arylradical according to above definition that is attached to an oxygenatom. The attachment to the compounds of the general formula is via theoxygen atom. Examples are phenyloxy, 2-naphthyloxy, 1-naphthyloxy,biphenyloxy, indanyloxy. Preferred is phenyloxy.

The term “heteroaryloxy” for the purposes of this invention refers to aheteroaryl radical according to above definition that is attached to anoxygen atom. The attachment to the compounds of the general formula isvia the oxygen atom. Examples are pyrrolyloxy, thienyloxy, furyloxy,imidazolyloxy, thiazolyloxy.

The term “carbonyl” or “carbonyl moiety” for the purposes of thisinvention refers to a —C(O)— group.

The term “alkylcarbonyl” for the purposes of this invention refers to a“alkyl-C(O)—” group, wherein alkyl is as defined herein.

The term “alkoxycarbonyl” or “alkyloxycarbonyl” for the purposes of thisinvention refers to a “alkyl-O—C(O)—” group, wherein alkyl is as definedherein.

The term “alkoxyalkyl” for the purposes of this invention refers to a“alkyl-O-alkyl-” group, wherein alkyl is as defined herein.

The term “haloalkyl” for the purposes of this invention refers to analkyl group as defined herein comprising at least one carbon atomsubstituent with at least one halogen as defined herein.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” forthe purposes of this invention refers to one or, where appropriate, aplurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl,chloro), or iodine (I, iodo) atoms. The designations “dihalogen”,“trihalogen” and “perhalogen” refer respectively to two, three and foursubstituents, where each substituent can be selected independently fromthe group consisting of fluorine, chlorine, bromine and iodine.“Halogen” preferably means a fluorine, chlorine or bromine atom.Fluorine is most preferred, when the halogens are substituted on analkyl (haloalkyl) or alkoxy group (e.g. CF₃ and CF₃O).

The term “hydroxyl” or “hydroxy” means an OH group.

The term “composition”, as in pharmaceutical composition, for thepurposes of this invention is intended to encompass a product comprisingthe active ingredient(s), and the inert ingredient(s) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound of thepresent invention and a pharmaceutically acceptable carrier.

The terms “administration of” and “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to the individualist need.

As used herein, the term “effective amount” refers to any amount of adrug or pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

All stereoisomers of the compounds of the invention are contemplated,either in a mixture or in pure or substantially pure form. The compoundsof the invention can have asymmetric centers at any of the carbon atoms.Consequently, they can exist in the form of their racemates, in the formof the pure enantiomers and/or diastereomers or in the form of mixturesof these enantiomers and/or diastereomers. The mixtures may have anydesired mixing ratio of the stereoisomers.

Thus, for example, the compounds of the invention which have one or morecenters of chirality and which occur as racemates or as diastereomermixtures can be fractionated by methods known per se into their opticalpure isomers, i.e. enantiomers or diastereomers. The separation of thecompounds of the invention can take place by column separation on chiralor nonchiral phases or by recrystallization from an optionally opticallyactive solvent or with use of an optically active acid or base or byderivatization with an optically active reagent such as, for example, anoptically active alcohol, and subsequent elimination of the radical.

The compounds of the invention may be present in the form of theirdouble bond isomers as “pure” E or Z isomers, or in the form of mixturesof these double bond isomers.

Where possible, the compounds of the invention may be in the form of thetautomers, such as keto-enol tautomers.

It is likewise possible for the compounds of the invention to be in theform of any desired prodrugs such as, for example, esters, carbonates,carbamates, ureas, amides or phosphates, in which cases the actuallybiologically active form is released only through metabolism. Anycompound that can be converted in vivo to provide the bioactive agent(i.e. compounds of the invention) is a prodrug within the scope andspirit of the invention.

Various forms of prodrugs are well known in the art and are describedfor instance in:

-   (i) Wermuth C G et al., Chapter 31: 671-696, The Practice of    Medicinal Chemistry, Academic Press 1996;-   (ii) Bundgaard H, Design of Prodrugs, Elsevier 1985; and-   (iii) Bundgaard H, Chapter 5: 131-191, A Textbook of Drug Design and    Development, Harwood Academic Publishers 1991.

Said references are incorporated herein by reference.

It is further known that chemical substances are converted in the bodyinto metabolites which may where appropriate likewise elicit the desiredbiological effect—

-   -   in some circumstances even in more pronounced form.

Any biologically active compound that was converted in vivo bymetabolism from any of the compounds of the invention is a metabolitewithin the scope and spirit of the invention.

There is furthermore intended that a compound of the invention includesisotope-labelled forms thereof. An isotope-labelled form of a compoundof the invention is identical to this compound apart from the fact thatone or more atoms of the compound have been replaced by an atom or atomshaving an atomic mass or mass number which differs from the atomic massor mass number of the atom which usually occurs naturally. Examples ofisotopes which are readily commercially available and which can beincorporated into a compound of the invention by well-known methodsinclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,fluorine and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²F, ³⁵S, ¹⁸F and ³⁶Cl, respectively. A compound of the invention, aprodrug, thereof or a pharmaceutically acceptable salt of either whichcontains one or more of the above-mentioned isotopes and/or otherisotopes of other atoms is intended to be part of the present invention.An isotope-labelled compound of the invention can be used in a number ofbeneficial ways. For example, an isotope-labelled compound of theinvention into which, for example, a radioisotope, such as ³H or ¹⁴C,has been incorporated is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to simple preparationand excellent detectability. Incorporation of heavier isotopes, forexample deuterium (²H), into a compound of the invention has therapeuticadvantages owing to the higher metabolic stability of thisisotope-labelled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder most circumstances would represent a preferred embodiment of thepresent invention. An isotope-labelled compound of the invention canusually be prepared by carrying out the procedures disclosed in thesynthesis schemes and the related description, in the example part andin the preparation part in the present text, replacing anon-isotope-labelled reactant by a readily available isotope-labelledreactant.

Deuterium (²H) can also be incorporated into a compound of the inventionfor the purpose in order to manipulate the oxidative metabolism of thecompound by way of the primary kinetic isotope effect. The primarykinetic isotope effect is a change of the rate for a chemical reactionthat results from exchange of isotopic nuclei, which in turn is causedby the change in ground state energies necessary for covalent bondformation after this isotopic exchange. Exchange of a heavier isotopeusually results in a lowering of the ground state energy for a chemicalbond and thus cause a reduction in the rate in rate-limiting bondbreakage. If the bond breakage occurs in or in the vicinity of asaddle-point region along the coordinate of a multi-product reaction,the product distribution ratios can be altered substantially. Forexplanation: if deuterium is bonded to a carbon atom at anon-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is successfully applied to a compoundof the invention that is susceptible to oxidation, the profile of thiscompound in vivo can be drastically modified and result in improvedpharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimise pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays currentlyavailable provide valuable information on the course of oxidativemetabolism of this type, which in turn permits the rational design ofdeuterated compounds of the invention with improved stability throughresistance to such oxidative metabolism. Significant improvements in thepharmacokinetic profiles of compounds of the invention are therebyobtained, and can be expressed quantitatively in terms of increases inthe in vivo half-life (t/2), concentration at maximum therapeutic effect(C_(max)), area under the dose response curve (AUC), and F; and in termsof reduced clearance, dose and materials costs.

The following is intended to illustrate the above: a compound of theinvention which has multiple potential sites of attack for oxidativemetabolism, for example benzylic hydrogen atoms and hydrogen atomsbonded to a nitrogen atom, is prepared as a series of analogues in whichvarious combinations of hydrogen atoms are replaced by deuterium atoms,so that some, most or all of these hydrogen atoms have been replaced bydeuterium atoms. Half-life determinations enable favourable and accuratedetermination of the extent of the extent to which the improve-ment inresistance to oxidative metabolism has improved. In this way, it isdetermined that the half-life of the parent compound can be extended byup to 100% as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of the invention can also beused to achieve a favourable modification of the metabolite spectrum ofthe starting compound in order to diminish or eliminate undesired toxicmetabolites. For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

The compounds of the invention can, if they have a sufficiently basicgroup such as, for example, a secondary or tertiary amine, be convertedwith inorganic and organic acids into salts. The pharmaceuticallyacceptable salts of the compounds of the invention are preferably formedwith hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid,phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonicacid, formic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid,oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid,racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid,lactic acid, citric acid, taurocholic acid, glutaric acid, stearic acid,glutamic acid or aspartic acid. The salts which are formed are, interalia, hydrochlorides, chlorides, hydrobromides, bromides, iodides,sulfates, phosphates, methanesulfonates, tosylates, carbonates,bicarbonates, formates, acetates, sulfoacetates, triflates, oxalates,malonates, maleates, succinates, tartrates, malates, embonates,mandelates, fumarates, lactates, citrates, glutarates, stearates,aspartates and glutamates. The stoichiometry of the salts formed fromthe compounds of the invention may moreover be an integral ornon-integral multiple of one.

The compounds of the invention can, if they contain a sufficientlyacidic group such as, for example, the carboxy, sulfonic acid,phosphoric acid or a phenolic group, be converted with inorganic andorganic bases into their physiologically tolerated salts. Examples ofsuitable inorganic bases are ammonium, sodium hydroxide, potassiumhydroxide, calcium hydroxide, and of organic bases are ethanolamine,diethanolamine, triethanolamine, ethylenediamine, t-butylamine,t-octylamine, dehydroabietylamine, cyclohexylamine,dibenzylethylene-diamine and lysine. The stoichiometry of the saltsformed from the compounds of the invention can moreover be an integralor non-integral multiple of one.

It is likewise possible for the compounds of the invention to be in theform of their solvates and, in particular, hydrates which can beobtained for example by crystallization from a solvent or from aqueoussolution. It is moreover possible for one, two, three or any number ofsolvate or water molecules to combine with the compounds of theinvention to give solvates and hydrates.

By the term “solvate” is meant a hydrate, an alcoholate, or othersolvate of crystallization.

It is known that chemical substances form solids which exist indifferent order states which are referred to as polymorphic forms ormodifications. The various modifications of a polymorphic substance maydiffer greatly in their physical properties. The compounds of theinvention can exist in various polymorphic forms and certainmodifications may moreover be metastable. All these polymorphic forms ofthe compounds are to be regarded as belonging to the invention.

The compounds of the invention are surprisingly characterized by astrong and/or selective modulation, preferably positive allostericmodulation (agonistic activity) of metabotrobic glutamate receptorsubtype-4 (mGluR4).

Due to their surprisingly strong and/or selective receptor modulation,the compounds of the invention can be advantageously administered atlower doses compared to other less potent or selective modulators of theprior art while still achieving equivalent or even superior desiredbiological effects. In addition, such a dose reduction mayadvantageously lead to less or even no medicinal adverse effects.Further, the high modulation selectivity of the compounds of theinvention may translate into a decrease of undesired side effects on itsown regardless of the dose applied.

The compounds of the invention being mGluR4 positive allostericmodulators generally have an half maximal effective concentration (EC₅₀)of less than about 100 μM, preferably less than about 10 μM, and mostpreferably less than about 1 μM.

The object of the present invention has surprisingly been solved inanother aspect by providing the use of a compound of the invention formodulating metabotropic glutamate receptor subtype 4 (mGluR4) and/oraltering glutamate level or glutamatergic signalling.

The terms “modulating, altering, modulation and/or alteration” areintended to refer for the purposes of the present invention to asfollows: “partial or complete activating, stimulating, activation and/orstimulation”. In this case, it is within the specialist knowledge of theaverage person skilled in the art to measure and determine suchactivating, stimulating, activation and/or stimulation by means of theusual methods of measurement and determination. Thus, a partialactivating, stimulating, activation and/or stimulation, for example, canbe measured and determined in relation to a complete activating,stimulating, activation and/or stimulation.

The object of the present invention has surprisingly been solved inanother aspect by providing a process for manufacturing a compound ofthe invention, comprising the steps of:

-   -   (a) reacting a compound of formula (II)

-   -   wherein    -   R₁, R₂ are as defined supra,    -   with a compound of formula (III)

-   -   wherein    -   X, R_(3a), R_(3b), R_(4a), R_(4b), R_(5a), R_(5b), R_(6a),        R_(6b) are as defined supra,    -   to yield the compound of formula (I)

-   -   wherein    -   R₁, R₂, X, R_(3a), R_(3b), R_(4a), R_(5b), R_(5a), R_(5b),        R_(6a), R_(6b) are as defined supra,    -   or    -   (b) reacting a compound of formula (IV)

-   -   wherein    -   X is OH or halogen, and    -   R₁ is as defined supra,    -   with a compound of formula (V)        Z—R₂  (V)    -   wherein    -   Z denotes halogen, boronic acid or a ester of boronic acid and    -   R₂ is as defined supra,    -   to yield the compound of formula (I)

-   -   wherein    -   R₁, R₂, X, R_(3a), R_(3b), R_(4a), R_(5b), R_(5a), R_(5b),        R_(6a), R_(6b) are as defined supra,    -   and optionally,    -   (c) converting one or more radicals R_(3a), R_(3b), R_(4a),        R_(4b), R_(5a), R_(5b), R_(6a), R_(6b) as defined supra into one        or more other radicals R_(3a), R_(3b), R_(4a), R_(4b), R_(5a),        R_(5b), R_(6a), R_(6b) as defined supra, e.g. by introducing a        heterocyclyl(alkyl) or an alkyl group,    -   and optionally    -   (d) converting a base or an acid of the compound of formula (I)        into a salt thereof.

Some crude products were subjected to standard chromatography usingsolvent mixtures containing methanol, ethanol, isopropanol, ethylacetate, n-hexane, cyclohexane, dichloromethane, n-heptane or petrolether, respectively.

For a further detailed description of the manufacturing processes,please refer also to the examples and the following general descriptionof the preferred conditions.

A physiologically acceptable salt of a compound of the invention canalso be obtained by isolating and/or treating the compound of theinvention obtained by the described reaction with an acid or a base.

The compounds of the invention and also the starting materials for theirpreparation are, are prepared by methods as described in the examples orby methods known per se, as described in the literature (for example instandard works, such as Houben-Weyl, Methoden der Organischen Chemie[Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; OrganicReactions, John Wiley & Sons, Inc., New York), to be precise underreaction conditions which are known and suitable for the said reactions.Use can also be made here of variants which are known per se, but arenot mentioned here in greater detail.

The starting materials for the claimed process may, if desired, also beformed in situ by not isolating them from the reaction mixture, butinstead immediately converting them further into the compounds of theinvention. On the other hand, it is possible to carry out the reactionstepwise.

Preferably, the reaction of the compounds is carried out in the presenceof a suitable solvent, which is preferably inert under the respectivereaction conditions. Examples of suitable solvents are hydrocarbons,such as hexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichlorethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone or butanone; amides, such as acetamide,dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidinone(NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethylsulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene;esters, such as ethyl acetate, or mixtures of the said solvents ormixtures with water. Polar solvents are in general preferred. Examplesfor suitable polar solvents are chlorinated hydrocarbons, alcohols,glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. Morepreferred are amides, especially dimethylformamide (DMF).

As stated above, the reaction temperature is between about −100° C. and300° C., depending on the reaction step and the conditions used.

Reaction times are generally in the range between some minutes andseveral days, depending on the reactivity of the respective compoundsand the respective reaction conditions. Suitable reaction times arereadily determinable by methods known in the art, for example reactionmonitoring. Based on the reaction temperatures given above, suitablereaction times generally lie in the range between 10 min and 48 hrs.

A base of a compound of the invention can be converted into theassociated acid-addition salt using an acid, for example by reaction ofequivalent amounts of the base and the acid in a preferably inertsolvent, such as ethanol, followed by evaporation. Suitable acids forthis reaction are, in particular, those which give physiologicallyacceptable salts. Thus, it is possible to use inorganic acids, forexample sulfuric acid, sulfurous acid, dithionic acid, nitric acid,hydrohalic acids, such as hydrochloric acid or hydrobromic acid,phosphoric acids, such as, for example, orthophosphoric acid, sulfamicacid, furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, hexanoic acid, octanoic acid, decanoic acid,hexadecanoic acid, octadecanoic acid, pivalic acid, diethylacetic acid,malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid,lactic acid, tartaric acid, malic acid, citric acid, gluconic acid,ascorbic acid, nicotinic acid, isonicotinic acid, methane- orethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonicacid, benzenesulfonic acid, trimethoxybenzoic acid, adamantanecarboxylicacid, p-toluenesulfonic acid, glycolic acid, embonic acid,chlorophenoxyacetic acid, aspartic acid, glutamic acid, proline,glyoxylic acid, palmitic acid, parachlorophenoxyisobutyric acid,cyclohexanecarboxylic acid, glucose 1-phosphate, naphthalenemono- and-disulfonic acids or laurylsulfuric acid.

Salts with physiologically unacceptable acids, for example picrates, canbe used to isolate and/or purify the compounds of the invention.

On the other hand, compounds of the invention can be converted into thecorresponding metal salts, in particular alkali metal salts or alkalineearth metal salts, or into the corresponding ammonium salts, using bases(for example sodium hydroxide, potassium hydroxide, sodium carbonate orpotassium carbonate). Suitable salts are furthermore substitutedammonium salts, for example the dimethyl-, diethyl- anddiisopropylammonium salts, monoethanol-, diethanol- anddiisopropanolammonium salts, cyclohexyl- and dicyclohexylammonium salts,dibenzylethylenediammonium salts, furthermore, for example, salts witharginine or lysine.

If desired, the free bases of the compounds of the invention can beliberated from their salts by treatment with strong bases, such assodium hydroxide, potassium hydroxide, sodium carbonate or potassiumcarbonate, so long as no further acidic groups are present in themolecule. In the cases where the compounds of the invention have freeacid groups, salt formation can likewise be achieved by treatment withbases. Suitable bases are alkali metal hydroxides, alkaline earth metalhydroxides or organic bases in the form of primary, secondary ortertiary amines.

Every reaction step described herein can optionally be followed by oneor more working up procedures and/or isolating procedures. Suitable suchprocedures are known in the art, for example from standard works, suchas Houben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart). Examples for suchprocedures include, but are not limited to evaporating a solvent,distilling, crystallization, fractionised crystallization, extractionprocedures, washing procedures, digesting procedures, filtrationprocedures, chromatography, chromatography by HPLC and dryingprocedures, especially drying procedures in vacuo and/or elevatedtemperature.

The object of the present invention has surprisingly been solved inanother aspect by providing a medicament comprising at least onecompound of the invention.

The object of the present invention has surprisingly been solved inanother aspect by providing a medicament comprising at least onecompound of the invention for use in the treatment and/or prophylaxis ofphysiological and/or pathophysiological conditions selected from thegroup consisting of: “condition which is affected or facilitated by theneuromodulatory effect of mGluR4 allosteric modulators, central nervoussystem disorders, addiction, tolerance or dependence, affectivedisorders, such as anxiety, agoraphobia, generalized anxiety disorder(GAD), obsessive-compulsive disorder (OCD), panic disorder,post-traumatic stress disorder (PTSD), social phobia, other phobias,substance-induced anxiety disorder, and acute stress disorder, mooddisorders, bipolar disorders (I & II), cyclothymic disorder, depression,dysthymic disorder, major depressive disorder, and substance-inducedmood disorder, psychiatric disease, such as psychotic disorders andattention-deficit/hyperactivity disorder, Parkinson's disease, andmovement disorders such as bradykinesia, rigidity, dystonia,drug-induced parkinsonism, dyskinesia, tardive dyskinesia,L-DOPA-induced dyskinesia, dopamine agonist-induced dyskinesia,hyperkinetic movement disorders, Gilles de la Tourette syndrome, restingtremor, action tremor, akinesia, akinetic-rigid syndrome, akathisia,athetosis, asterixis, tics, postural instability, postencephaliticparkinsonism, muscle rigidity, chorea and choreaform movements,spasticity, myoclonus, hemiballismus, progressive supranuclear palsy,restless legs syndrome, and periodic limb movement disorder, cognitivedisorders such as delirium, substance-induced persisting delirium,dementia, dementia due to HIV disease, dementia due to Huntington'sdisease, dementia due to Parkinson's disease, Parkinsonian-ALS dementialcomplex, dementia of the Alzheimer's type, substance-induced persistingdementia, and mild cognitive impairment, neurological disorders such asneurodegeneration, neurotoxicity or ischemia such as stroke, spinal cordinjury, cerebral hypoxia, intracranial hematoma, memory impairment,Alzheimer's disease, dementia, delirium tremens, other forms ofneurodegeneration, neurotoxicity, and ischemia, inflammation and/orneurodegeneration resulting from traumatic brain injury, inflammatorycentral nervous system disorders, such as multiple sclerosis forms suchas benign multiple sclerosis, relapsing-remitting multiple sclerosis,secondary progressive multiple sclerosis, primary progressive multiplesclerosis, and progressive-relapsing multiple sclerosis, migraine,epilepsy and tremor, temporal lobe epilepsy, epilepsy secondary toanother disease or injury such as chronic encephalitis, traumatic braininjury, stroke or ischemia, medulloblastomas, inflammatory orneuropathic pain, metabolic disorders associated with glutamatedysfunction, type 2 diabetes, diseases or disorders of the retina,retinal degeneration or macular degeneration, diseases or disorders ofthe gastrointestinal tract including gastroesophageal reflux disease(GERD), lower esophageal sphincter diseases or disorders, diseases ofgastrointestinal motility, colitis, Crohn's disease or irritable bowelsyndrome (IBS), cancers.” A corresponding use for the preparation of amedicament for the treatment and/or prophylaxis of the aforementionedconditions is intended to be comprised. A corresponding method oftreatment administering at least one compound of the invention to apatient in need thereof is also intended to be comprised.

Compounds of the invention may be used in combination with one or moreother active substances (ingredients, drugs) in the treatment,prevention, suppression or amelioration of diseases or conditions forwhich compounds of the invention or the other substances have utility.Typically the combination of the drugs is safer or more effective thaneither drug alone, or the combination is safer or more effective thanwould it be expected based on the additive properties of the individualdrugs. Such other drug(s) may be administered, by a route and in anamount commonly used contemporaneously or sequentially with a compoundof the invention. When a compound of the invention is usedcontemporaneously with one or more other drugs, a combination productcontaining such other drug(s) and the compound of the invention ispreferred. However, combination therapy also includes therapies in whichthe compound of the invention and one or more other drugs areadministered on different overlapping schedules. It is contemplated thatwhen used in combination with other active ingredients, the compound ofthe present invention or the other active ingredient or both may be usedeffectively in lower doses than when each is used alone. Accordingly,the pharmaceutical compositions of the present invention include thosethat contain one or more other active ingredients, in addition to acompound of the invention.

Examples of other active substances (ingredients, drugs) that may beadministered in combination with a compound of the invention, and eitheradministered separately or in the same pharmaceutical composition,include, but are not limited to the compounds classes and specificcompounds listed in the following:

levodopa, levodopa with selective extracerebral decarboxylaseinhibitors, carbidopa, entacapone, COMT inhibitors, dopamine agonists,dopamine receptor agonists, apomorphine, anticholinergics, cholinergicagonists, butyrophenone neuroleptic agents, diphenylbutylpiperidineneuroleptic agents, heterocyclic dibenzazepine neuroleptic agents,indolone neuroleptic agents, phenothiazine neuroleptic agents,thioxanthene neuroleptic agents, NMDA receptor antagonists, MAO-Binhibitors, mGluR3 PAMs or agonists, mGluR4 PAMs or agonists, mGluR5antagonist or A2A antagonists.

In another aspect of the invention, a medicament according to aboveaspects and embodiments is provided, wherein in such medicamentcomprises at least one additional pharmacologically active substance(drug, ingredient).

In a preferred embodiment the at least one pharmacologically activesubstance is a substance as described herein.

In another aspect of the invention, a medicament according to aboveaspects and embodiments is provided, wherein the medicament is appliedbefore and/or during and/or after treatment with at least one additionalpharmacologically active substance.

In a preferred embodiment the at least one pharmacologically activesubstance is a substance as described herein.

In another aspect of the invention, a pharmaceutical compositioncomprising a therapeutically effective amount of at least one compoundof the invention is provided.

In a preferred embodiment, the pharmaceutical composition contains atleast one additional compound selected from the group consisting ofphysiologically acceptable excipients, auxiliaries, adjuvants, diluents,carriers and/or additional pharmaceutically active substance other thanthe compounds of the invention.

In another aspect of the invention, a pharmaceutical composition isdisclosed which comprises at least one compound of the invention, atleast one pharmacologically active substance other than the compounds ofthe invention as described herein; and a pharmaceutically acceptablecarrier.

A further embodiment of the present invention is a process for themanufacture of said pharmaceutical compositions, characterized in thatone or more compounds according to the invention and one or morecompounds selected from the group consisting of solid, liquid orsemiliquid excipients, auxiliaries, adjuvants, diluents, carriers andpharmaceutically active agents other than the compounds according to theinvention, are converted in a suitable dosage form.

In another aspect of the invention, a kit is provided comprising atherapeutically effective amount of at least one compound of theinvention and/or at least one pharmaceutical composition as describedherein and a therapeutically effective amount of at least one furtherpharmacologically active substance other than the compounds of theinvention.

The pharmaceutical compositions of the present invention may beadministered by any means that achieve their intended purpose. Forexample, administration may be by oral, parenteral, topical, enteral,intravenous, intramuscular, inhalant, nasal, intraarticular,intraspinal, transtracheal, transocular, subcutaneous, intraperitoneal,transdermal, or buccal routes. Alternatively, or concurrently,administration may be by the oral route. The dosage administered will bedependent upon the age, health, and weight of the recipient, kind ofconcurrent treatment, if any, frequency of treatment, and the nature ofthe effect desired. Parenteral administration is preferred. Oraladministration is especially preferred.

Suitable dosage forms include, but are not limited to capsules, tablets,pellets, dragees, semi-solids, powders, granules, suppositories,ointments, creams, lotions, inhalants, injections, cataplasms, gels,tapes, eye drops, solution, syrups, aerosols, suspension, emulsion,which can be produced according to methods known in the art, for exampleas described below:

tablets: mixing of active ingredient/s and auxiliaries, compression ofsaid mixture into tablets (direct compression), optionally granulationof part of mixture before compression.

capsules: mixing of active ingredient/s and auxiliaries to obtain aflowable powder, optionally granulating powder, fillingpowders/granulate into opened capsules, capping of capsules.

semi-solids (ointments, gels, creams): dissolving/dispersing activeingredient/s in an aqueous or fatty carrier; subsequent mixing ofaqueous/fatty phase with complementary fatty/aqueous phase,homogenization (creams only).

suppositories (rectal and vaginal): dissolving/dispersing activeingredients in carrier material liquified by heat (rectal: carriermaterial normally a wax; vaginal: carrier normally a heated solution ofa gelling agent), casting said mixture into suppository forms, annealingand withdrawal suppositories from the forms.

aerosols: dispersing/dissolving active agent/s in a propellant, bottlingsaid mixture into an atomizer.

In general, non-chemical routes for the production of pharmaceuticalcompositions and/or pharmaceutical preparations comprise processingsteps on suitable mechanical means known in the art that transfer one ormore compounds of the invention into a dosage form suitable foradministration to a patient in need of such a treatment. Usually, thetransfer of one or more compounds of the invention into such a dosageform comprises the addition of one or more compounds, selected from thegroup consisting of carriers, excipients, auxiliaries and pharmaceuticalactive ingredients other than the compounds of the invention. Suitableprocessing steps include, but are not limited to combining, milling,mixing, granulating, dissolving, dispersing, homogenizing, castingand/or compressing the respective active and non-active ingredients.Mechanical means for performing said processing steps are known in theart, for example from Ullmann's Encyclopedia of Industrial Chemistry,5th Edition. In this respect, active ingredients are preferably at leastone compound of the invention and one or more additional compounds otherthan the compounds of the invention, which show valuable pharmaceuticalproperties, preferably those pharmaceutical active agents other than thecompounds of the invention, which are disclosed herein.

Particularly suitable for oral use are tablets, pills, coated tablets,capsules, powders, granules, syrups, juices or drops, suitable forrectal use are suppositories, suitable for parenteral use are solutions,preferably oil-based or aqueous solutions, furthermore suspensions,emulsions or implants, and suitable for topical use are ointments,creams or powders. The compounds of the invention may also belyophilised and the resultant lyophilisates used, for example, for thepreparation of injection preparations. The preparations indicated may besterilised and/or comprise assistants, such as lubricants,preservatives, stabilisers and/or wetting agents, emulsifiers, salts formodifying the osmotic pressure, buffer substances, dyes, flavours and/ora plurality of further active ingredients, for example one or morevitamins.

Suitable excipients are organic or inorganic substances, which aresuitable for enteral (for example oral), parenteral or topicaladministration and do not react with the compounds of the invention, forexample water, vegetable oils, benzyl alcohols, alkylene glycols,polyethylene glycols, glycerol triacetate, gelatine, carbohydrates, suchas lactose, sucrose, mannitol, sorbitol or starch (maize starch, wheatstarch, rice starch, potato starch), cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, magnesium stearate, talc, gelatine, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose,polyvinyl pyrrolidone and/or vaseline.

If desired, disintegrating agents may be added such as theabove-mentioned starches and also carboxymethyl-starch, cross-linkedpolyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such assodium alginate. Auxiliaries include, without limitation,flow-regulating agents and lubricants, for example, silica, talc,stearic acid or salts thereof, such as magnesium stearate or calciumstearate, and/or polyethylene glycol. Dragee cores are provided withsuitable coatings, which, if desired, are resistant to gastric juices.For this purpose, concentrated saccharide solutions may be used, whichmay optionally contain gum arabic, talc, polyvinyl pyrrolidone,polyethylene glycol and/or titanium dioxide, lacquer solutions andsuitable organic solvents or solvent mixtures. In order to producecoatings resistant to gastric juices or to provide a dosage formaffording the advantage of prolonged action, the tablet, dragee or pillcan comprise an inner dosage and an outer dosage component me latterbeing in the form of an envelope over the former. The two components canbe separated by an enteric layer, which serves to resist disintegrationin the stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids and mixtures of polymeric acids with such materialsas shellac, acetyl alcohol, solutions of suitable cellulose preparationssuch as acetyl-cellulose phthalate, cellulose acetate orhydroxypropylmethyl-cellulose phthalate, are used. Dye stuffs orpigments may be added to the tablets or dragee coatings, for example,for identification or in order to characterize combinations of activecompound doses.

Suitable carrier substances are organic or inorganic substances whichare suitable for enteral (e.g. oral) or parenteral administration ortopical application and do not react with the novel compounds, forexample water, vegetable oils, benzyl alcohols, polyethylene glycols,gelatin, carbohydrates such as lactose or starch, magnesium stearate,talc and petroleum jelly. In particular, tablets, coated tablets,capsules, syrups, suspensions, drops or suppositories are used forenteral administration, solutions, preferably oily or aqueous solutions,furthermore suspensions, emulsions or implants, are used for parenteraladministration, and ointments, creams or powders are used for topicalapplication. The compounds of the invention can also be lyophilized andthe lyophilizates obtained can be used, for example, for the productionof injection preparations.

The preparations indicated can be sterilized and/or can containexcipients such as lubricants, preservatives, stabilizers and/or wettingagents, emulsifiers, salts for affecting the osmotic pressure, buffersubstances, colorants, flavourings and/or aromatizers. They can, ifdesired, also contain one or more further active compounds, e.g. one ormore vitamins.

Other pharmaceutical preparations, which can be used orally includepush-fit capsules made of gelatine, as well as soft, sealed capsulesmade of gelatine and a plasticizer such as glycerol or sorbitol. Thepush-fit capsules can contain the active compounds in the form ofgranules, which may be mixed with fillers such as lactose, binders suchas starches, and/or lubricants such as talc or magnesium stearate and,optionally, stabilizers. In soft capsules, the active compounds arepreferably dissolved or suspended in suitable liquids, such as fattyoils, or liquid paraffin. In addition, stabilizers may be added.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally include aqueoussolutions, suitably flavoured syrups, aqueous or oil suspensions, andflavoured emulsions with edible oils such as cottonseed oil, sesame oil,coconut oil or peanut oil, as well as elixirs and similar pharmaceuticalvehicles. Suitable dispersing or suspending agents for aqueoussuspensions include synthetic and natural gums such as tragacanth,acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatine.

Suitable formulations for parenteral administration include aqueoussolutions of the active compounds in water-soluble form, for example,water-soluble salts and alkaline solutions. In addition, suspensions ofthe active compounds as appropriate oily injection suspensions may beadministered. Suitable lipophilic solvents or vehicles include fattyoils, for example, sesame oil, or synthetic fatty acid esters, forexample, ethyl oleate or triglycerides or polyethylene glycol-400 (thecompounds are soluble in PEG-400).

Aqueous injection suspensions may contain substances, which increase theviscosity of the suspension, including, for example, sodiumcarboxymethyl cellulose, sorbitol, and/or dextran, optionally, thesuspension may also contain stabilizers.

For administration as an inhalation spray, it is possible to use spraysin which the active ingredient is either dissolved or suspended in apropellant gas or propellant gas mixture (for example CO₂ orchlorofluorocarbons). The active ingredient is advantageously used herein micronized form, in which case one or more additional physiologicallyacceptable solvents may be present, for example ethanol. Inhalationsolutions can be administered with the aid of conventional inhalers.

Possible pharmaceutical preparations, which can be used rectallyinclude, for example, suppositories, which consist of a combination ofone or more of the active compounds with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,or paraffin hydrocarbons. In addition, it is also possible to usegelatine rectal capsules, which consist of a combination of the activecompounds with a base. Possible base materials include, for example,liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.

For use in medicine, the compounds of the present invention will be inthe form of pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds of the invention or oftheir pharmaceutically acceptable salts. Suitable pharmaceuticallyacceptable salts of the compounds of this invention include acidaddition salts which may, for example be formed by mixing a solution ofthe compound according to the invention with a solution of apharmaceutically acceptable acid such as hydrochloric acid, sulphuricacid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid,acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid,carbonic acid or phosphoric acid. Furthermore, where the compounds ofthe invention carry an acidic moiety, suitable pharmaceuticallyacceptable salts thereof may include alkali metal salts, e.g. sodium orpotassium salts; alkaline earth metal salts, e.g. calcium or magnesiumsalts; and salts formed with suitable organic bases, e.g. quaternaryammonium salts.

The pharmaceutical preparations can be employed as medicaments in humanand veterinary medicine. As used herein, the term “effective amount”means that amount of a drug or pharmaceutical agent that will elicit thebiological or medical response of a tissue, system, animal or human thatis being sought, for instance, by a researcher or clinician.Furthermore, the term “therapeutically effective amount” means anyamount which, as compared to a corresponding subject who has notreceived such amount, results in improved treatment, healing,prevention, or amelioration of a disease, disorder, or side effect, or adecrease in the rate of advancement of a disease or disorder. The termalso includes within its scope amounts effective to enhance normalphysiological function. Said therapeutic effective amount of one or moreof the compounds of the invention is known to the skilled artisan or canbe easily determined by standard methods known in the art.

The compounds of the invention and the additional active substances aregenerally administered analogously to commercial preparations. Usually,suitable doses that are therapeutically effective lie in the rangebetween 0.0005 mg and 1000 mg, preferably between 0.005 mg and 500 mgand especially between 0.5 mg and 100 mg per dose unit. The daily doseis preferably between about 0.001 mg/kg and 10 mg/kg of body weight.

Those of skill will readily appreciate that dose levels can vary as afunction of the specific compound, the severity of the symptoms and thesusceptibility of the subject to side effects. Some of the specificcompounds are more potent than others. Preferred dosages for a givencompound are readily determinable by those of skill in the art by avariety of means. A preferred means is to measure the physiologicalpotency of a given compound.

For the purpose of the present invention, all mammalian species areregarded as being comprised. In a preferred embodiment, such mammals areselected from the group consisting of “primate, human, rodent, equine,bovine, canine, feline, domestic animals, cattle, livestock, pets, cow,sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat,dog, guinea pig, hamster, rat, mouse”. More preferably, such mammals arehumans. Animal models are of interest for experimental investigations,providing a model for treatment of human diseases.

The specific dose for the individual patient depends, however, on themultitude of factors, for example on the efficacy of the specificcompounds employed, on the age, body weight, general state of health,the sex, the kind of diet, on the time and route of administration, onthe excretion rate, the kind of administration and the dosage form to beadministered, the pharmaceutical combination and severity of theparticular disorder to which the therapy relates. The specifictherapeutic effective dose for the individual patient can readily bedetermined by routine experimentation, for example by the doctor orphysician, which advises or attends the therapeutic treatment.

In the case of many disorders, the susceptibility of a particular cellto treatment with the subject compounds may be determined by in vitrotesting. Typically a culture of the cell is combined with a subjectcompound at varying concentrations for a period of time sufficient toallow the active agents to show a relevant reaction, usually betweenabout one hour and one week. For in vitro testing, cultured cells from abiopsy sample may be used.

Even without further details, it is assumed that a person skilled in theart will be able to utilise the above description in the broadest scope.The preferred embodiments should therefore merely be regarded asdescriptive disclosure, which is absolutely not limiting in any way.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means that, if necessary, the solventis removed, water is added if necessary, the pH is adjusted, ifnecessary, to between 2 and 10, depending on the constitution of the endproduct, the mixture is extracted with ethyl acetate or dichloromethane,the phases are separated, the organic phase is washed with saturatedNaHCO₃ solution, if desired with water and saturated NaCl solution, isdried over sodium sulfate, filtered and evaporated, and the product ispurified by chromatography on silica gel, by preparative HPLC and/or bycrystallisation. The purified compounds are, if desired, freeze-dried.

NMR spectra were acquired on a Varian ^(Unity)Inova 400 MHz, a VarianVNMRS 500 MHz or a Bruker AVIII 400 MHz NMR spectrometer using residualsignal of deuterated solvent as internal reference. Chemical shifts (δ)are reported in ppm relative to tetramethylsilane. 1H NMR data arereported as follows: chemical shift (multiplicity, coupling constants,and number of hydrogens). Multiplicity is abbreviated as follows: s(singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br(broad).

The microwave chemistry is performed on a single mode microwave reactorInitiator 8 from Biotage.

Analytical LC/MS data provided in the examples are given with retentiontime, purity and/or mass in m/z. Analytical LC/MS was performed usingone of the following 4 methods:

Method A (Rapid LC): A Shimadzu Shim-pack XR-ODS, 3.0×30 mm, 2.2 μm, wasused at a temperature of 50° C. and at a flow rate of 1.5 mL/min, 2 μLinjection, mobile phase: (A) water with 0.1% formic acid and 1%acetonitrile, mobile phase (B) methanol with 0.1% formic acid; retentiontime given in minutes. Method details: (I) runs on a Binary Pump G1312Bwith UV/Vis diode array detector G1315C and Agilent 6130 massspectrometer in positive and negative ion electrospray mode withUV-detection at 220 and 254 nm with a gradient of 15-95% (B) in a 2.2min linear gradient (II) hold for 0.8 min at 95% (B) (III) decrease from95-15% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 15%(B).

Method B (Polar Stop-Gap): An Agilent Zorbax Bonus RP, 2.1×50 mm, 3.5μm, was used at a temperature of 50° C. and at a flow rate of 0.8mL/min, 2 μL injection, mobile phase: (A) water with 0.1% formic acidand 1% acetonitrile, mobile phase (B) methanol with 0.1% formic acid;retention time given in minutes. Method details: (I) runs on a BinaryPump G1312B with UV/Vis diode array detector G1315C and Agilent 6130mass spectrometer in positive and negative ion electrospray mode withUV-detection at 220 and 254 nm with a gradient of 5-95% (B) in a 2.5 minlinear gradient (II) hold for 0.5 min at 95% (B) (III) decrease from95-5% (B) in a 0.1 min linear gradient (IV) hold for 0.29 min at 5% (B).

Method C: A Waters Sunfire C18, 3.5 μm, 3.0×50 mm column was used at aflow rate of 1 mL/min, 2 μL injection, mobile phase (A) water with 0.1%trifluoroacetic acid, mobile phase (B) acetonitrile with 0.1%trifluoroacetic acid; retention time given in minutes. Method details:(I) runs on a Binary Pump G1312A (Agilent) with UV/Vis diode arraydetector G1315B (Agilent) and Agilent G1956B (SL) mass spectrometer inpositive ESI mode with UV-detection at 215 and 254 nm with a gradient of5-95% (B) in a 4.5 min linear gradient (II) hold for 1 min at 95% (B)(III) decrease from 95-5% (B) in a 0.1 min linear gradient (IV) hold for0.9 min at 5% (B).

Method D: A Xbridge C8, 3.5 μm, 4.5×50 mm column was used at a flow rateof 2 mL/min, 5 μL injection, mobile phase (A) water with 0.1%trifluoroacetic acid, mobile phase (B) acetonitrile with 0.1%trifluoroacetic acid; retention time given in minutes. Method details:(I) runs on a Binary Pump G1312A (Agilent) with UV/Vis diode arraydetector G1315B (Agilent) with UV-detection at 215 and 254 nm with agradient of 5-100% (B) in a 8 min linear gradient (II) hold for 0.1 minat 100% (B) (III) decrease from 100-5% (B) in a 0.4 min linear gradient(IV) hold for 1.5 min at 5% (B).

Preparative HPLC was performed using a system controlled by Chromeleonsoftware and consisting of two Varian PrepStar Model 218 Pumps, a VarianProStar Model 320 UV/Vis detector, a SEDEX 55 ELSD detector, and aGilson 215 liquid handler. Typical HPLC mobile phases consist of waterand methanol. The standard column is a Varian Dynamax 21.4 mm diameterMicrosorb Guard-8 C18 column.

The contents of all cited references are hereby incorporated byreference in their entirety. The invention is explained in more detailby means of the following examples without, however, being restrictedthereto.

EXAMPLES I. Synthesis of Selected Compounds of the Invention

The following compounds were synthesized and characterized. However, itlies in the knowledge of a person skilled in the art to prepare andcharacterize these compounds differently.

Example 1 Synthesis of compound Compound 5(5-Methyl-2,3-diphenyl-quinoxaline)

To a stirred solution of 1,2-diphenyl-ethane-1,2-dione (100 mg, 0.48mmol) and 3-methyl-benzene-1,2-diamine (70 mg, 0.57 mmol) inacetonitrile (5 mL) was added iodine (12 mg; 0.05 mmol). The mixture wasstirred for 10 minutes at room temperature. The solution wasconcentrated to dryness under reduce pressure and the resultant residuewas redissolved in ethyl acetate (20 mL). The organic phase was washedwith saturated aqueous sodium thiosulfate (10 mL) and brine (10 mL), andconcentrated under reduce pressure. The residue was purified bychromatography using dichloromethane/ethyl acetate (0% to 10%) as eluentto give title compound 5-methyl-2,3-diphenyl-quinoxaline (117 mg; 83%)as a pale yellow solid; LCMS (ESI) 297 (M+H); HPLC 100%, RT: 4.60 min;¹H NMR (400 MHz, CHLOROFORM-d) δ ppm: 2.85 (s, 3H), 7.27-7.38 (m, 6H),7.48-7.60 (m, 5H), 7.61-7.67 (m, 1H), 7.96-8.03 (m, 1H).

The following compounds were synthesized in an analogous manner:

Compound 7 (1-(2,3-Diphenyl-quinoxalin-5-yl)-ethanone)

Compound 9 (2,3-Bis-(4-fluoro-phenyl)-quinoxaline)

Example 2 Synthesis of Compound 1 (2-Phenyl-3-quinolin-4-yl-quinoxaline)

Step 1: A mixture of oxo-phenyl-acetic acid (500 mg, 3.33 mmol) andbenzene-1,2-diamine (792 mg, 7.33 mmol) in ethanol (15 mL) was stirredfor 2 h at room temperature. The reaction became a homogeneous yellowsolution, and then started a yellow solid started precipitating. Thereaction mixture was filtered. The solid was purified by chromatographyusing dichloromethane/ethyl acetate (0% to 10%) as eluent to give3-phenyl-quinoxalin-2-ol (370 mg; 50%) as a yellow solid; LCMS (ESI) 223(M+H); HPLC 100%, RT: 2.14 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 12.57(br s, 1H), 8.25-8.36 (m, 1H), 7.79-7.89 (m, 1H), 7.43-7.59 (m, 3H),7.26-7.39 (m, 2H).

Step 2: A mixture of 3-phenyl-quinoxalin-2-ol (50 mg; 0.22 mmol) andbromotripyrrolidinophosphonium hexafluorophosphate (126 mg; 0.27 mmol)in dioxane (2 mL) was placed in a sealed tube. Nitrogen gas was bubbledthrough the reaction mixture for 2 min, before triethylamine (0.09 mL;0.67 mmol) was added and the reaction mixture was stirred at roomtemperature for 4 h. Quinoline-4-boronic acid (78 mg; 0.45 mmol), sodiumcarbonate (119 mg; 1.12 mmol) andbis(triphenylphosphene)palladium(II)chloride (7.9 mg; 0.01 mmol) wereadded, followed by water (1 mL) and the tube was sealed. The reactionmixture was heated at 100° C. overnight. The reaction mixture was cooledto room temperature, diluted with water (2 mL), brine (2 mL) and ethylacetate (100 mL). The aqueous layer was extracted with ethyl acetate (50mL). The combined organic layer was dried over anhydrous sodium sulfate,filtered and evaporated under reduced pressure. The residue was purifiedby chromatography using heptane/ethyl acetate (0% to 100%) as eluent togive title compound 2-phenyl-3-quinolin-4-yl-quinoxaline (30 mg; 40%) asa yellow solid; LCMS (ESI) 334 (M+H); HPLC 98.9%, RT: 4.29 min; ¹H NMR(400 MHz, DMSO-d₆) δ ppm: 8.92 (d, J=4.3 Hz, 1H), 8.26-8.31 (m, 1H),8.18-8.23 (m, 1H), 8.07 (d, J=8.5 Hz, 1H), 7.93-8.04 (m, 2H), 7.66-7.77(m, 2H), 7.56 (d, J=4.3 Hz, 1H), 7.49 (ddd, J=8.3, 7.0, 1.1 Hz, 1H),7.39-7.44 (m, 2H), 7.16-7.28 (m, 3H).

The following compounds were synthesized in an analogous manner:

Compound 2 (4-(3-Phenyl-quinoxalin-2-yl)-phenol); LCMS (ESI) 299 (M+H);HPLC 100%, RT: 2.95 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 9.76 (br s,1H), 8.00-8.25 (m, 2H), 7.69-7.96 (m, 2H), 7.45-7.57 (m, 2H), 7.34-7.43(m, 3H), 7.31 (d, J=8.6 Hz, 2H), 6.72 (d, J=8.6 Hz, 2H)

Compound 4 (2-(3,4-Difluoro-phenyl)-3-(1H-indol-4-yl)-quinoxaline); LCMS(ESI) 358 (M+H); HPLC 97.9%, RT: 4.39 min; ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm: 6.43 (ddd, J=3.3, 1.8, 0.8 Hz, 1H), 6.96 (dt,J=10.1, 8.3 Hz, 1H), 7.09-7.15 (m, 1H), 7.19-7.25 (m, 3H), 7.41-7.49 (m,2H), 7.78-7.88 (m, 2H), 8.18-8.25 (m, 2H), 8.30 (br s, 1 H)

Compound 6 (2-Phenyl-3-quinolin-8-yl-quinoxaline); LCMS (ESI) 334 (M+H);HPLC 97.8%, RT: 3.94 min; ¹H NMR (400 MHz, DMSO-d₆) δ ppm: 8.55 (dd,J=4.1, 1.8 Hz, 1H), 8.29-8.34 (m, 1H), 8.21-8.26 (m, 1H), 8.14-8.19 (m,1H), 8.08 (td, J=7.2, 1.4 Hz, 2H), 7.88-7.97 (m, 2H), 7.71-7.80 (m, 1H),7.34-7.43 (m, 3H), 7.03-7.15 (m, 3H)

Compound 10 (2-(3,4-Difluoro-phenyl)-3-phenyl-quinoxaline); LCMS (ESI)319 (M+H); HPLC 100%, RT: 2.74 min; ¹H NMR (400 MHz, CHLOROFORM-d) δppm: 8.11-8.30 (m, 2H), 7.76-7.90 (m, 2H), 7.65 (td, J=8.4, 6.4 Hz, 1H),7.47-7.57 (m, 2H), 7.31-7.45 (m, 3H), 6.97-7.07 (m, 1H), 6.73 (ddd,J=9.8, 8.9, 2.4 Hz, 1H)

Example 3 Synthesis of Compound 3(1-(3-Phenyl-quinoxalin-2-yl)-piperidin-4-ol)

Step 1: Prepared as described in example 2 step 1.

Step 2: To a solution of 3-phenyl-quinoxalin-2-ol (1.00 g, 4.50 mmol) inthionyl chloride (10 mL, 140 mmol) was added three drops of DMF. Thereaction mixture was heated at 85 to 90° C. for 2 h. The excess thionylchloride was removed under reduced pressure. The remaining solid wasdissolved in toluene (50 mL) and concentrated under reduced pressurethree times to give 2-chloro-3-phenyl-quinoxaline (976 mg; 90%) as anoff-white solid which was used without purification in the next step.

Step 3: A mixture of 2-chloro-3-phenyl-quinoxaline (50 mg, 0.21 mmol),piperidin-4-ol (25 mg, 0.25 mmol) and ethyldiisopropylamine (0.11 mL,0.62 mmol) in DMF (1 mL) was placed in a sealed tube. The reactionmixture was allowed to stir at 100° C. for 18 h. The reaction mixturewas cooled to room temperature, diluted with water and extracted withethyl acetate. The combined organic layer was dried over anhydroussodium sulfate, filtered and evaporated under reduced pressure. Theresidue was purified by chromatography using dichloromethane/ethylacetate as eluent to give title compound1-(3-phenyl-quinoxalin-2-yl)-piperidin-4-ol (30 mg; 47%) as a yellowsolid; LCMS (ESI) 306 (M+H); HPLC 99.0%, RT: 4.05 min; ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm: 7.95-8.05 (m, 3H), 7.82 (dd, J=8.3, 0.9 Hz, 1H),7.61 (ddd, J=8.3, 6.9, 1.4 Hz, 1H), 7.42-7.54 (m, 4H), 3.85 (td, J=8.8,4.4 Hz, 1H), 3.67 (dt, J=13.2, 3.9 Hz, 2H), 2.97 (ddd, J=13.2, 10.1, 2.9Hz, 2H), 1.89 (dt, J=9.2, 3.7 Hz, 2H), 1.57-1.65 (m, 2H), 1.46 (d, J=4.1Hz, 1H).

Example 4 Synthesis of compound 8(2,3-Diphenyl-5,6,7,8-tetrahydro-quinoxaline)

Step 1: A mixture of 1,2-diphenyl-ethane-1,2-dione (1.00 g, 4.76 mmol)and cis/trans-cyclohexane-1,2-diamine (0.58 mL, 4.76 mmol) in ethanol(25 mL) was heated for 3 hours at 50° C. The reaction mixture was cooledto room temperature and concentrated under reduced pressure to give2,3-diphenyl-4a,5,6,7,8,8a-hexahydro-quinoxaline (1.50 g; quantitative),which was used in the next step without purification.

Step 2: To a stirred solution of2,3-diphenyl-4a,5,6,7,8,8a-hexahydro-quinoxaline (100 mg, 0.35 mmol) inethanol (5 mL) was added ferric chloride (113 mg, 0.69 mmol) and thereaction mixture was heated for 3 hours at 50° C. The reaction mixturewas cooled to room temperature, and concentrated under reduced pressure.The residue was purified by chromatography using dichloromethane/ethylacetate as eluent to give title compound2,3-diphenyl-5,6,7,8-tetrahydro-quinoxaline as a white solid; LCMS (ESI)287 (M+H); HPLC 100%, RT: 3.98 min; ¹H NMR (400 MHz, CHLOROFORM-d) δppm: 7.36-7.45 (m, 4H), 7.24-7.32 (m, 6H), 3.00-3.14 (m, 4H), 1.94-2.08(m, 4H).

TABLE 1 hrmGluR4/HEK29 3T-hmGluR4 (EC₅₀) A > 10 μM Compound LC/MS LC/MSm/z B = 1-10 μM No. RT (min) [M + H] C < 1 μM 1 1.80 334 C 2 1.76 299 C3 1.76 306 C 4 2.32 358 B 5 2.53 297 B 6 1.71 334 B 7 B 8 2.03 287 B 9 B10 2.00 319 B

II. Biological Assays

HEK-293 mGluR4 Cells cAMP Assay with EC20 L-Glutamate

Using mGluR4 suspension cell format, 10 μM Forskolin (final conc.) usedto induce the production of cAMP.

Test the positive allosteric activity of the compounds of the inventionat EC₂₀ (2.3 μM for mGluR4 and 4.3 μM for mGluR6) L-Glutamate,

cAMP dymanic2 kit is intended for the direct quantitative determinationof cAMP and its principle is based on HTRF technology.

Reagents:

Cells: HEK293T mGluR4 cells from Multispan, cat#C1191a lot#C1191a-040910

Culture Media: DMEM+GlutaMAX1+10% dialyzed FBS, 100 mM Sodium Pyruvate,1 ug/ml puromycin.

Glutamine Starvation Media: DMEM without GlutaMax for plating the cells(glutamine starvation overnight). DMEM high Glucose, without phenol red,glutamine, or sodium pyruvate+10% dialyzed FBS, 100 mM Sodium Pyruvate,1 ug/ml puromycin, 10 mM Hepes.

Hanks' balanced Salt Solution, HBSS from Invitrogen

Greiner 384 well white low volume high base plate (784075)

cAMP dynamic2 from Cisbio Bioassays

Glutamate: L-Glutamaic acid, monosodium salt, Monohydrate, 98%, fromSigma-Aldrich

Cell Preparation: split cells at 80%-90% confluence. The following day,rinse the cells with DMEM without GlutaMax and change to GlutamineStarvation Media. Incubate overnight.

Assay:

Prepare compound plate: Perform compound serial dilution (uses Matrix4341 plate), using the Bravo liquid handling platform protocol (compoundserial dilution) which adds DMSO to columns 1-24 (except cols. 3 and13). Serial dilute compounds located in columns 3 and 13 at a 1:3 ratio;10 points (10 ul of 3 mM compound into 20 ul DMSO). Use the Bravo liquidhandling platform to transfer 1 ul from the serial dilution plate intoMatrix 4314 plate to create stamp plates.

Prepare Compound Dilution Buffer:

Dilute 20 mM Forskolin (in DMSO) stock solution in HBSS buffer to make a20 uM solution (forskolin buffer; 2× solution). To the forskolin buffer,add glutamate to a concentration of 8 uM (compound dilution buffer;2×EC20 glutamate and forskolin).

Using a multidrop, add 50 ul/well of compound dilution buffer to columns1-22 of the 2 ul compound stamp plate. Columns 23 and 24 receiveforskolin buffer containing 400 uM glutamate (EC100 glutamate; 2×solution). Columns 1 and 2 receive compound dilution buffer containingEC20 glutamate, which is the basal control. Add a glutamate doseresponse to row P of compound plate. Prepare the dose response by serialdiluting glutamate at a 1:3 ratio in forskolin buffer starting at 2 mMglutamate (2×). Dilute the glutamate 9 times and transfer to compoundplate.

Prepare Cell Plates:

Harvest cells: Rinse cells with pre-warmed HBSS-10 mM HEPES (without CaMg) and dissociate the cells from the flask with versene. Centrifuge thecells, remove the supernatant and suspend in pre-warmed HBSS+10 mMHepes. Count the cells and centrifuge. Remove the supernatant andsuspend the cells in HBSS+Hepes (with Ca Mg) at a density of 400,000cells/ml.

Perform Assay:

Dispense 5 ul from the diluted compound plate into Greiner low volumecell plate using the Bravo liquid handling platform. Using a Multidropwith the small tubing cassette, dispense 5 ul of cells (2000 cells/well)onto the compounds contained in the low volume plates. Incubate thecells at 37° C., 5% CO₂ for 30 minutes in the incubator.

Assay for cAMP:

Prepare cAMP-d2 and anti-cAMP-Crytate according to the instructions forthe two step assay (see Cisbio manual) and add 10 ul of the mixedreagent to each well of the assay plate using the Multidrop. Incubate atroom temperature for 60 minutes and read on the Envision plate readerusing the mGluR low volume cAMP HTRF 384 well protocol. The readout isthe calculated fluorescence ratio (665 nM/615 nM*10000).

The measured half maximal effective concentration (EC₅₀) of thecompounds of the invention is displayed in table 1.

The invention claimed is:
 1. A method for modulating metabotropicglutamate receptor subtype 4 and/or altering glutamate level orglutamatergic signaling in a subject, comprising administering to asubject in need thereof an effective amount of a compound of formula(I):

or a pharmaceutically acceptable salt thereof, wherein: X each denotesC; R₁, and R₂ independently from each other denote aryl, heteroaryl orheterocyclyl, which can optionally be substituted by one or moreidentical or different substituents T; R_(3a), R_(3b), R_(4a), R_(4b),R_(5a), R_(5b), R_(6a), and R_(6b) independently from each other denotesubstituent T, if the individual X is C; or if the individual X is N,then one of the R_(3a), R_(3b), R_(4a), R_(4b), R_(5a), R_(5b), R_(6a),and R_(6b) substituents is absent and the other one of the R_(3a),R_(3b), R_(4a), R_(4b), R_(5a), R_(5b), R_(6a), and R_(6b) substituentsdenotes substituent T or forms a double bond with one of the R_(3a),R_(3b), R_(4a), R_(4b), R_(5a), R_(5b), R_(6a), and R_(6b) substituentsof an adjacent X; T independently from each other denotes H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, OH, CN, NO₂,NYY, CF₃, OCF₃, alkyl-OH, alkyl-NYY, alkyl-CN, O-alkyl, O-cycloalkyl,O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl,O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-heterocyclyl, C(O)-alkyl,C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl,C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl,C(O)-alkyl-heterocyclyl, C(O)O-alkyl, C(O)O-cycloalkyl,C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl, C(O)O-heteroaryl,C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl, C(O)O-alkyl-heterocyclyl,C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl,C(O)NH-alkyl-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl,C(O)NH-heterocyclyl, C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl,NHC(O)-cycloalkyl, NHC(O)-alkyl-cycloalkyl, NHC(O)-aryl,NHC(O)-alkyl-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl,NHC(O)-heterocyclyl, NHC(O)-alkyl-heterocyclyl, O-alkyl-NYY, C(O)H,C(O)OY, C(O)NY-alkyl-NYY, or C(O)NYY, wherein alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl moieties can optionally besubstituted by one or more identical or different substituents Z; Yindependently from each other denotes H, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, or heterocyclylalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl can optionally be substituted by oneor more identical or different substituents Z; and Z independently fromeach other denotes alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen,OH, CN, NO₂, NH₂, NH-alkyl, N(alkyl)₂, NH-alkyl-OH, NH-alkyl-O-alkyl,NH-alkyl-aryl, CF₃, OCF₃, alkyl-OH, alkyl-NH₂, alkyl-NH-alkyl,alkyl-N(alkyl)₂, alkyl-CN, alkyl-C(O)-heterocyclyl, O-alkyl,O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl,O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-heterocyclyl, O-alkyl-NH₂,C(O)H, C(O)OH, C(O)NH-alkyl-NH₂, C(O)NH₂, C(O)—C(O)—NH₂,C(O)-alkyl-NH-alkyl, C(O)-alkyl-NH-alkyl-O-alkyl, C(O)-alkyl,C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl,C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl,C(O)-alkyl-heterocyclyl, C(O)-heterocyclyl-alkyl, C(O)O-alkyl,C(O)O-cycloalkyl, C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl,C(O)O-heteroaryl, C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl,C(O)O-alkyl-heterocyclyl, C(O)NH-alkyl, C(O)NH-cycloalkyl,C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl, C(O)NH-alkyl-aryl,C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl, C(O)NH-heterocyclyl,C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl, NHC(O)-cycloalkyl,NHC(O)-alkyl-cycloalkyl, NHC(O)-aryl, NHC(O)-alkyl-aryl,NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl, NHC(O)-heterocyclyl,NHC(O)-alkyl-heterocyclyl C(O)NH-aryl-halogen, C(O)NH-aryl-O-alkyl,C(O)N(alkyl)-aryl, C(O)N(aryl)₂, S-alkyl, S-cycloalkyl,S-alkyl-cycloalkyl, S-aryl, S-alkyl-aryl, S-heteroaryl,S-alkyl-heteroaryl, S-heterocyclyl, or S-alkyl-heterocyclyl.
 2. Themethod according to claim 1, wherein in the compound of formula (I)

denotes


3. The method according to claim 2, wherein in the compound of formula(I) T independently from each other denotes H, F, Cl, methyl, methoxy,hydroxy, ethoxy, isopropoxy, hydroxy-methyl, methyl-carbonyl,4-methyl-piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,4-methyl-piperazin-1-yl-carbonyl,(2-hydroxy-1,1-dimethyl-ethyl)-carboxylic acid amide, pyrrolidin-1-yl-carbonyl, carboxylic acid cyclopentylamide,piperidin-1-yl-carbonyl, carboxylic acid cyclohexylamide,azetidin-1-yl-carbonyl, carboxylic acid cyclohexylmethylamide,carboxylic acid (3-methyl-butyl)-amide, carboxylic acid(5-methyl-isoxazol-3-yl)-amide, carboxylic acid pyridin-2-ylamide,carboxylic acid pyridin-3-ylamide, carboxylic acid pyridin-4-ylamide,carboxylic acid (4-hydroxy-cyclohexyl)-amide, carboxylic acid(2-cyano-ethyl) -amide, carboxylic acid (2-hydroxy-propyl)-amide,carboxylic acid cyclopropylmethyl-amide, carboxylic acid methylamide,carboxylic acid dimethylamide, carboxylic acid (2-hydroxy-ethyl)-amide,carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide, carboxylic acidthiazol-2-ylamide, carboxylic acid ethyl ester, carboxylic acidisopropyl ester, carboxylic acid[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide, carboxylic acid(2-dimethylamino-ethyl)-amide, carboxylic acid(6-chloro-benzothiazol-2-yl) -amide, methoxymethyl,4-methyl-piperazin-1-yl-methyl, morpholin-4-ylmethyl,pyrrolidin-1-yl-methyl, 4-hydroxy-piperdin-1-yl,[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-aminomethyl, methylaminomethyl,2-pyrrolidin-1-yl-ethoxy, 1-methyl-pyrrolidin-3-yloxy,4-methyl-piperazin-1-yl)-propoxy,2-dimethylamino-ethyloxy,3-dimethylamino-propyloxy,4-methyl-piperazin-1-yl)-ethoxy, 2-morpholin-4-yl-ethoxy,3-morpholin-4-yl-propoxy, 1-methyl-tetrazol-5-yl, or2-methyltetrazol-5-yl.
 4. The method according to claim 1, wherein inthe compound of formula (I) R₁, and R₂ independently from each otherdenote phenyl, furanyl, pyridinyl, thiophenyl, pyrrolidinyl,naphthalenyl, morpholinyl, piperazinyl, azetidinyl, piperidinyl,quinolinyl, indolyl, indazolyl or benzooxazolonyl, which can optionallybe substituted by one or more identical or different substituents T. 5.A method according to claim 1, wherein the subject suffers from aphysiological and/or pathophysiological condition selected from thegroup consisting of anxiety, rigidity, an addiction, a phobia, a tic acentral nervous system disorder, a tolerance disorder, a dependencedisorder, an affective disorder, a mood disorder, a bipolar disorder, apsychotic disorder, a movement disorder, a cognitive disorder, aneurological disorder, a metabolic disorder associated with glutamatedysfunction, a disorder of the retina, a disorder of thegastrointestinal tract, a lower esophageal sphincter disorder, a diseaseof the retina, a disease of the gastrointestinal tract, a loweresophageal disease and a disease of gastrointestinal motility.
 6. Themethod according to claim 5, wherein the central nervous system disorderor movement disorder is selected from the group consisting of aninflammatory central nervous system disorder, a hyperkinetic movementdisorder and a choreaform ,movement.
 7. The method according to claim 5,wherein the compound of formula (I) is administered before and/or duringand/or after treatment with at least one additional pharmacologicallyactive substance.
 8. The method according to claim 1, wherein thesubject suffers from a physiological and/or pathophysiological conditionselected from the group consisting of agoraphobia, generalized anxietydisorder, obsessive-compulsive disorder, panic disorder, post-traumaticstress disorder, social phobia, substance-induced anxiety disorder,acute stress disorder, bipolar disorder cyclothymic disorder,depression, dysthymic disorder, major depressive disorder, psychiatricdisease, substance-induced mood disorder,attention-deficit/hyperactivity disorder, Parkinson's disease,bradykinesia dystonia, drug-induced parkinsonism, dyskinesia, Gilles dela Tourette syndrome, tremor, akinesia, akinetic-rigid syndrome,akathisia, athetosis, asterixis, postural instability, postencephalitic,parkinsonism, muscle rigidity, chorea, spasticity, myoclonus,hemiballismus, progressive supranuclear palsy, restless legs syndrome,periodic limb movement disorder, parkinsonian-amyotrophic lateralsclerosis demential complex, mild cognitive impairment,neurodegeneration, neurotoxicity, ischemia, stroke, spinal cord injury,cerebral hypoxia, intracranial hematoma, memory impairment, Alzheimer'sdisease, dementia, delirium, inflammation, multiple sclerosis, migraine,epilepsy, traumatic brain injury, medulloblastoma, inflammatory pain,neuropathic pain, type 2 diabetes, retinal degeneration, maculardegeneration, gastroesophageal, reflux disease, colitis, Crohn's diseaseand irritable bowel syndrome.
 9. The method according to claim 8,wherein the bipolar disorder, dyskinesia, tremor, neurodegenerationdementia, delirium, inflammation, multiple sclerosis or epilepsy isselected from the group consisting of bipolar disorder I, bipolardisorder II, tardive dyskinesia, L-3,4-dihydroxphenylalanine-induceddyskinesia, dopamine agonist-induced dyskinesia, resting tremor, actiontremor, neurodegeneration resulting from traumatic brain injury,dementia due to human immunodeficiency virus disease , dementia due toHuntington's disease, dementia due to Parkinson's disease, dementia ofthe Alzheimer's type and substance-induced persisting dementia, deliriumtremens, substance-induced persisting delirium, inflammation resultingfrom traumatic brain injury, benign multiple sclerosis,relapsing-remitting multiple sclerosis, primary progressive multiplesclerosis, secondary progressive multiple sclerosis,progressive-relapsing multiple sclerosis, temporal lobe epilepsy,secondary to another disease and epilepsy secondary to injury.
 10. Amethod for modulating metabotropic glutamate receptor subtype 4 and/oraltering glutamate level or glutamatergic signaling in a subject,comprising administering to a subject in need thereof an effectiveamount of a compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: X each denotesC; R₁, and R₂ independently from each other are selected from the groupconsisting of: phenyl, furan-2-yl, furan-3-yl, 4-dimethylamino-phenyl,2-fluorophenyl, 4-fluorophenyl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 4-hydroxy-phenyl, thiophen-2-yl, thiophen-3-yl,4-methoxy-phenyl, 4-ethoxy-phenyl, 4-ethyl-phenyl,4-fluoro-3-methyl-phenyl, 4-methylsulfanyl-phenyl,4-trifluoromethoxy-phenyl, 3,4-difluorophenyl, 4-formylphenyl,4-tert-butyl-phenyl, 4-isopropyl-phenyl, pyrrolidin-1-yl,3-chloro-4-methoxy-phenyl, 3-chloro-4-methyl-phenyl,4-cyanomethyl-phenyl, 2-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 6-methoxy-naphthalen-1-yl, 3,4-dichlorophenyl,morpholin-4-yl, 4-dimethylamino-phenyl, 4-methyl-piperazin-1-yl,azetidin-1-yl, piperidin-1-yl, quinolin-4-yl, quinolin-8-yl,4-hydroxymethyl-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, indol-4-yl,4-amino-phenyl, indazol-5-yl, 4-hydroxymethyl-phenyl, andbenzooxazol-2-on-6-yl R_(3a), R_(3b), R_(4a), R_(4b), R_(5a), R_(5b),R_(6a), and R_(6b) independently from each other denote substituent T,if the individual X is C; or if the individual X is N, then one of theR_(3a), R_(3b)R_(4a), R_(4b), R_(5a), R_(5b), R_(6a), and R_(6b)substituents is absent and the other one of the R_(3a), R_(3b), R_(4a),R_(4b), R_(5a), R_(5b), R_(6a), and R_(6b) substituents denotessubstituent T or forms a double bond with one of the R_(3a), R_(3b),R_(4a), R_(4b), R_(5a), R_(5b), R_(6a), and R_(6b) substituents of anadjacent X; T independently from each other denotes H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, OH, CN, NO₂,NYY, CF₃, OCF₃, alkyl-OH, alkyl-NYY alkyl-CN O-alkyl, O-cycloalkyl,O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl,O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-heterocyclyl, C(O)-alkyl,C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl,C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl,C(O)-alkyl-heterocyclyl, C(O)O-alkyl, C(O)O-cycloalkyl,C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl, C(O)O-heteroaryl,C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl, C(O)O-alkyl-heterocyclyl,C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl,C(O)NH-alkyl-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl,C(O)NH-heterocyclyl, C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl,NHC(O)-cycloalkyl, NHC(O)-alkyl-cycloalkyl, NHC(O)-aryl,NHC(O)-alkyl-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl,NHC(O)-heterocyclyl, NHC(O)-alkyl-heterocyclyl, O-alkyl-NYY, C(O)H,C(O)OY, C(O)NY-alkyl-NYY, or C(O)NYY, wherein alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl moieties can optionally besubstituted by one or more identical or different substituents Z; Yindependently from each other denotes H, alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl, or heterocyclylalkyl, wherein alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclyl and heterocyclylalkyl can optionally be substituted by oneor more identical or different substituents Z; and Z independently fromeach other denotes alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen,OH, CN, NO₂, NH₂, NH-alkyl, N(alkyl)₂, NH-alkyl-OH, NH-alkyl-O-alkyl,NH-alkyl-aryl, CF₃, OCF₃, alkyl-OH, alkyl-NH₂ alkyl-NH-alkyl,alkyl-N(alkyl)₂, alkyl-CN, alkyl-C(O)-heterocyclyl, O-alkyl,O-cycloalkyl, O-alkyl-cycloalkyl, O-aryl, O-alkyl-aryl, O-heteroaryl,O-alkyl-heteroaryl, O-heterocyclyl, O-alkyl-heterocyclyl, O-alkyl-NH₂,C(O)H, C(O)OH, C(O)NH-alkyl-NH₂, C(O)NH₂, C(O)—C(O)—NH₂,C(O)-alkyl-NH-alkyl, C(O)-alkyl-NH-alkyl-O-alkyl, C(O)-alkyl,C(O)-cycloalkyl, C(O)-alkyl-cycloalkyl, C(O)-aryl, C(O)-alkyl-aryl,C(O)-heteroaryl, C(O)-alkyl-heteroaryl, C(O)-heterocyclyl,C(O)-alkyl-heterocyclyl, C(O)-heterocyclyl-alkyl, C(O)O-alkyl,C(O)O-cycloalkyl, C(O)O-alkyl-cycloalkyl, C(O)O-aryl, C(O)O-alkyl-aryl,C(O)O-heteroaryl, C(O)O-alkyl-heteroaryl, C(O)O-heterocyclyl,C(O)O-alkyl-heterocyclyl, C(O)NH-alkyl, C(O)NH-cycloalkyl,C(O)NH-alkyl-cycloalkyl, C(O)NH-aryl, C(O)NH-alkyl-aryl,C(O)NH-heteroaryl, C(O)NH-alkyl-heteroaryl, C(O)NH-heterocyclyl,C(O)NH-alkyl-heterocyclyl, NHC(O)-alkyl, NHC(O)-cycloalkyl,NHC(O)-alkyl-cycloalkyl, NHC(O)-aryl, NHC(O)-alkyl-aryl,NHC(O)-heteroaryl, NHC(O)-alkyl-heteroaryl, NHC(O)-heterocyclyl,NHC(O)-alkyl-heterocyclyl, C(O)NH-aryl-halogen, C(O)NH-aryl-O-alkyl,C(O)N(alkyl)-aryl, C(O)N(aryl)₂, S-alkyl, S-cycloalkyl,S-alkyl-cycloalkyl, S-aryl, S-alkyl-aryl, S-heteroaryl,S-alkyl-heterocyclyl, S-heterocyclyl,or S-alkyl-hetercyclyl.
 11. Themethod according to claim 10, wherein in the compound of formula (I)

denotes

R₁, and R₂ independently from each other are selected from the groupconsisting of: phenyl, furan-2-yl, furan-3-yl, 4-dimethylamino-phenyl,2-fluorophenyl, 4-fluorophenyl, pyridin-2-yl, pyridin-3-yl,pyridin-4-yl, 4-hydroxy-phenyl, thiophen-2-yl, thiophen-3-yl,4-methoxy-phenyl, 4-ethoxy-phenyl, 4-ethyl-phenyl,4-fluoro-3-methyl-phenyl, 4-methylsulfanyl-phenyl,4-trifluoromethoxy-phenyl, 3,4-difluorophenyl, 4-formylphenyl,4-tert-butyl-phenyl, 4-isopropyl-phenyl, pyrrolidin-1-yl,3-chloro-4-methoxy-phenyl, 3-chloro-4-methyl-phenyl,4-cyanomethyl-phenyl, 2-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 6-methoxy-naphthalen-1-yl, 3,4-dichlorophenyl,morpholin-4-yl, 4-dimethylamino-phenyl, 4-methyl-piperazin-1-yl,azetidin-1-yl, piperidin-1-yl, quinolin-4-yl, quinolin-8-yl,4-hydroxymethyl-piperidin-1-yl, 4-hydroxy-piperidin-1-yl, indol-4-yl,4-acetamide, 4-(2,2,2-trifluoro)-acetamide, 4-amino-phenyl,indazol-5-yl, 4-hydroxymethyl-phenyl, and benzooxazol-2-on-6-yl; and Tindependently from each other denotes H, F, Cl, methyl, methoxy,hydroxy, ethoxy, isopropoxy, hydroxy-methyl, methyl-carbonyl,4-methyl-piperidin-1-yl-carbonyl, morpholin-4-yl-carbonyl,4-methyl-piperazin-1-yl-carbonyl,(2-hydroxy-1,1-dimethyl-ethyl)-carboxylic acid amide,pyrrolidin-1-yl-carbonyl, carboxylic acid cyclopentylamide,piperidin-1-yl-carbonyl, carboxylic acid cyclohexylamide,azetidin-1-yl-carbonyl, carboxylic acid cyclohexylmethylamide,carboxylic acid (3-methyl-butyl)-amide, carboxylic acid(5-methyl-isoxazol-3-yl)-amide, carboxylic acid pyridin-2-ylamide,carboxylic acid pyridin-3-ylamide, carboxylic acid pyridin-4-ylamide,carboxylic acid (4-hydroxy-cyclohexyl)-amide, carboxylic acid(2-cyano-ethyl)-amide, carboxylic acid (2-hydroxy-propyl)-amide,carboxylic acid cyclopropylmethyl-amide, carboxylic acid methylamide,carboxylic acid dimethylamide, carboxylic acid (2-hydroxy-ethyl)-amide,carboxylic acid (2-hydroxy-1-methyl-ethyl)-amide, carboxylic acidthiazol-2-ylamide, carboxylic acid ethyl ester, carboxylic acidisopropyl ester, carboxylic acid[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-amide, carboxylic acid(2-dimethylamino-ethyl)-amide, carboxylic acid(6-chloro-benzothiazol-2-yl)-amide, methoxymethyl,4-methyl-piperazin-1-yl-methyl, morpholin-4-ylmethyl,pyrrolidin-1-yl-methyl, 4-hydroxy-piperdin-1-yl,[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-aminomethyl, methylaminomethyl,2-pyrrolidin-1-yl-ethoxy, 1-methyl-pyrrolidin-3-yloxy,4-methyl-piperazin-1-yl)-propoxy, 2-dimethylamino-ethyloxy,3-dimethylamino-propyloxy, 4-methyl-piperazin-1-yl)-ethoxy,2-morpholin-4-yl-ethoxy, 3-morpholin-4-yl-propoxy,1-methyl-tetrazol-5-yl, or 2-methyltetrazol-5-yl.
 12. The methodaccording to claim 10, wherein the subject suffers from a physiologicaland/or pathophysiological condition selected from the group consistingof anxiety, rigidity, an addiction, a phobia, a tic, a central nervoussystem disorder, a tolerance disorder, a dependence disorder, anaffective disorder, a mood disorder, a bipolar disorder, a psychoticdisorder, a movement disorder, a cognitive disorder, a neurologicaldisorder, a metabolic disorder associated with glutamate dysfunction, adisorder of the retina, a disorder of the gastrointestinal tract, alower esophageal sphincter disorder, a disease of the retina, a diseaseof the gastrointestinal tract, a lower esophageal sphincter disease anda disease of gastrointestinal motility.
 13. The method according toclaim 12, wherein the central nervous system disorder or movementdisorder is selected from the group consisting of an inflammatorycentral nervous system disorder, a hyperkinetic movement disorder and achoreaform movement.
 14. The method according to claim 10, wherein thesubject suffers from a physiological and/or pathophysiological conditionselected from the group consisting of agoraphobia, generalized anxietydisorder, obsessive-compulsive disorder, panic disorder, post-traumaticstress disorder, social phobia, substance-induced anxiety disorder,acute stress disorder, bipolar disorder, cyclothymic disorder,depression, dysthymic disorder, major depressive disorder, psychiatricdisease, substance-induced mood disorder,attention-deficit/hyperactivity disorder, Parkinson's disease,bradykinesia, dystonia, drug-induced parkinsonism, dyskinesia, Gilles dela Tourette syndrome, tremor, akinesia, akinetic-rigid syndrome,akathisia, athetosis, asterixis, postural instability, postencephaliticparkinsonism, muscle rigidity, chorea, spasticity, myoclonus,hemiballismus, progressive supranuclear palsy, restless legs syndrome,periodic limb movement disorder, parkinsonian-amyotrophic lateralsclerosis demential complex, mild cognitive impairment,neurodegeneration, neurotoxicity, ischemia, stroke, spinal cord injury,cerebral hypoxia, intracranial hematoma, memory impairment, Alzheimer'sdisease, dementia, delirium, inflammation, multiple sclerosis, migraine,epilepsy, traumatic brain injury, medulloblastoma, inflammatory pain,neuropathic pain, type 2 diabetes, retinal degeneration, maculardegeneration, gastroesophageal reflux disease, colitis, Crohn's diseaseand irritable bowel syndrome.
 15. The method according to claim 14,wherein the bipolar disorder, dyskinesia, tremor, neurodegeneration,dementia, delirium, inflammation, multiple sclerosis or epilepsy isselected from the group consisting of bipolar disorder I, bipolardisorder II, tardive dyskinesia, L-3,4-dihydroxyphenylalanine-induceddyskinesia, dopamine agonist-induced dyskinesia, resting tremor, actiontremor, neurodegeneration resulting from traumatic brain injury,dementia due to human immunodeficiency virus disease, dementia due toHuntington's disease, dementia due to Parkinson's disease, dementia ofthe Alzheimer's type and substance-induced persisting dementia, deliriumtremens, substance-induced persisting delirium, inflammation resultingfrom traumatic brain injury, benign multiple sclerosis,relapsing-remitting multiple sclerosis, primary progressive multiplesclerosis, secondary progressive multiple sclerosis,progressive-relapsing multiple sclerosis, temporal lobe epilepsy,epilepsy secondary to another disease and epilepsy secondary to injury.16. A method for modulating metabotropic glutamate receptor subtype 4and/or altering glutamate level or glutamatergic signaling in a subject,comprising administering to a subject in need thereof an effectiveamount of a compound selected from the group consisting of:2-phenyl-3-quinolin-4-ylquinoxaline; 4-(3-phenylquinoxalin-2-yl)phenol;1-(3-phenylquinoxalin-2-yl)piperidin-4-ol;2-(3,4-difluorophenyl)-3-(1H-indol-4-yl)quinoxaline;5-methyl-2,3-diphenylquinoxaline; 2-phenyl-3-quinolin-8-ylquinoxaline;1-(2,3-diphenylquinoxalin-5-yl)ethanone;2,3-diphenyl-5,6,7,8-tetrahydroquinoxaline,2,3-bis-(2-fluorophenyl)quinoxaline; and2-(3,4-difluorophenyl)-3-phenylquinoxaline, or a pharmaceuticallyacceptable salt thereof.
 17. The method according to claim 16, whereinthe subject suffers from a physiological and/or pathophysiologicalcondition selected from the group consisting of anxiety, rigidity, anaddiction, a phobia, a tic, a central nervous system disorder, atolerance disorder, a dependence disorder, an affective disorder, a mooddisorder, a bipolar disorder, a psychotic disorder, a movement disorder,a cognitive disorder, a neurological disorder, a metabolic disorderassociated with glutamate dysfunction, a disorder of the retina, adisorder of the gastrointestinal tract, a lower esophageal sphincterdisorder, a disease of the retina, a disease of the gastrointestinaltract, a lower esophageal sphincter disease and a disease ofgastrointestinal motility.
 18. The method according to claim 17, whereinthe central nervous system disorder or movement disorder is selectedfrom the group consisting of an inflammatory central nervous systemdisorder, a hyperkinetic movement disorder and a choreaform movement.19. The method according to claim 16, wherein the subject suffers from aphysiological and/or pathophysiological condition selected from thegroup consisting of agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic disorder, post-traumatic stressdisorder, social phobia, substance-induced anxiety disorder, acutestress disorder, bipolar disorder, cyclothymic disorder, depression,dysthymic disorder, major depressive disorder, psychiatric disease,substance-induced mood disorder, attention-deficit/hyperactivitydisorder, Parkinson's disease, bradykinesia, dystonia, drug-inducedparkinsonism, dyskinesia, Gilles de la Tourette syndrome, tremor,akinesia, akinetic-rigid syndrome, akathisia, athetosis, asterixis,postural instability, postencephalitic parkinsonism, muscle rigidity,chorea, spasticity, myoclonus, hemiballismus, progressive supranuclearpalsy, restless legs syndrome, periodic limb movement disorder,parkinsonian-amyotrophic lateral sclerosis demential complex, mildcognitive impairment, neurodegeneration, neurotoxicity, ischemia,stroke, spinal cord injury, cerebral hypoxia, intracranial hematoma,memory impairment, Alzheimer's disease, dementia, delirium,inflammation, multiple sclerosis, migraine, epilepsy, traumatic braininjury, medulloblastoma, inflammatory pain, neuropathic pain, type 2diabetes, retinal degeneration, macular degeneration, gastroesophagealreflux disease, colitis, Crohn's disease and irritable bowel syndrome.20. The method according to claim 19, wherein the bipolar disorder,dyskinesia, tremor, neurodegeneration, dementia, delirium, inflammation,multiple sclerosis or epilepsy is selected from the group consisting ofbipolar disorder I, bipolar disorder II, tardive dyskinesia,L-3,4-dihydroxyphenylalanine-induced dyskinesia, dopamineagonist-induced dyskinesia, resting tremor, action tremor,neurodegeneration resulting from traumatic brain injury, dementia due tohuman immunodeficiency virus disease, dementia due to Huntington'sdisease, dementia due to Parkinson's disease, dementia of theAlzheimer's type and substance-induced persisting dementia, deliriumtremens, substance-induced persisting delirium, inflammation resultingfrom traumatic brain injury, benign multiple sclerosis,relapsing-remitting multiple sclerosis, primary progressive multiplesclerosis, secondary progressive multiple sclerosis,progressive-relapsing multiple sclerosis, temporal lobe epilepsy,epilepsy secondary to another disease and epilepsy secondary to injury.